Antibodies neutralizing GM-CSF for use in the treatment of rheumatoid arthritis or as analgesics

ABSTRACT

The invention relates to neutralizing antibodies of GM-CSF and compositions comprising the same for use in the treatment of inflammatory disorders such as rheumatoid arthritis according to specific dosing regimen. The invention relates also to neutralizing antibodies of GM-CSF and compositions comprising the same for use in the treatment of pain, e.g. pain experienced in inflammatory disorders such as rheumatoid arthritis, according to specific dosage regimen.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 14/913,578, filed Feb. 22, 2016, now U.S. Pat. No.10,745,475, which is the national stage of International Application No.PCT/EP2014/068489, filed internationally on Sep. 1, 2014, which claimsthe benefit of U.S. Provisional Patent Application No. 61/871,900, filedAug. 30, 2013, and U.S. Provisional Patent Application No. 61/871,904,filed Aug. 30, 2013, the disclosures of which are hereby incorporated byreference in their entireties for all purposes.

SUBMISSION OF SEQUENCE LISTING AS ASCII TEXT FILE

The content of the following submission on ASCII text file isincorporated herein by reference in its entirety: a computer readableform (CRF) of the Sequence Listing (file name: 794112000101SEQLIST.TXT,date recorded: Aug. 17, 2020, size: 85 KB).

TECHNICAL FIELD

The present invention relates to antibodies and functional fragmentsthereof which neutralize the activity of human granulocyte macrophagecolony stimulating factor (GM-CSF) for use as active ingredients,particularly in drugs for treating rheumatoid arthritis. The inventionfurther relates to pharmaceutical compositions comprising suchantibodies and functional fragments thereof as well as to methods oftreatment of a patient in need thereof using such pharmaceuticalcompositions. The invention relates also to the preparation ofmedicaments for the treatment of rheumatoid arthritis with specificdosing. The invention relates also to antibodies and functionalfragments thereof which neutralize the activity of human granulocytemacrophage colony stimulating factor for use as active ingredients inanalgesics. The invention further relates to pharmaceutical compositionscomprising such antibodies and functional fragments thereof as well asto methods of pain treatment of a patient in need thereof using suchanalgesic pharmaceutical compositions.

TECHNICAL BACKGROUND

Rheumatoid arthritis (RA) is an autoimmune disease characterized by thepresence of autoantibodies, systemic inflammation and persistentsynovitis affecting primarily cartilage and bone of small and midsizedjoints. Various inflammatory cells, including macrophages andneutrophils infiltrate the joint. These activated cells release aplethora of inflammatory cytokines and enzymes damaging local tissues.An important inflammatory mediator in RA is Granulocyte MacrophageColony Stimulating Factor (GM-CSF) as it is involved in the activationof the innate arm of the immune system, which comprises macrophages,neutrophils, granulocytes, eosinophils and dendritic cells, all of whichcontribute to progression of RA. The absence of GM-CSF was found toreduce dramatically the severity of arthritis development in theantigen-induced mouse model. There is evidence that GM-CSF is producedin RA synovium and that levels of this cytokine can be measured in RAsynovial fluid, suggesting that it plays a direct or indirect role inthe pathogenesis of said disease. Further, studies have demonstrated theefficacy of systemic neutralization of GM-CSF using an anti-mouse GM-CSFmonoclonal antibody in an acute and in a chronic mouse model ofstreptococcal cell wall-induced arthritis. Previous publicationsrelating to other RA models have reported that also in collagen-inducedarthritis, and arthritis induced by methylated bovine serum albumin,treatment with a neutralizing anti-GM-CSF monoclonal antibody (mAb)decreased disease severity, whereas GM-CSF injection into miceexacerbated the disease. Further, it has been shown that administrationof GM-CSF to animals suffering from experimentally induced diseases(e.g. collagen-induced arthritis, etc.; cf. e.g. Bischof, R. J. et al.Clin Exp Immunol., 2000 February; 119(2): 361-367) or to patientsafflicted with diseases, such as Felty's syndrome, may worsen diseasesymptoms (Hazenberg B P C, et al.; Blood, 1989; 83:876-82). Thus, theadministration of pharmaceuticals comprising GM-CSF antagonists may bean effective way to substitute or complement commonly used treatment ofautoimmune diseases such as RA.

Despite enhanced management of RA during the last decades, it has becomeclear that early diagnosis and aggressive step-up therapy resulting inreduction in disease activity is crucial in order to control diseaseprogression and for bringing patients into a stage of low diseaseactivity or remission. In some trials, the proportion of early RApatients that can achieve remission/low disease activity may be around50% over one to two years but in daily clinical practice remissionfigures are lower and so far no drug has succeeded in curing RA whichfor most patients is a permanent chronic disease. Stable efficacy inlong-term treatment is therefore a need in many patients on DMARDs andbiologics, and there is accordingly also a need to improve safety overlong-term administration of drugs. Further, in RA patients symptoms suchas structural joint damage persist and do not completely resolve upontreatment. Accordingly, there is a need for new medicaments, which actin patients suffering from RA, for example moderate, moderate-to-severeor severe RA.

An additional problem in the treatment of RA patients is thatconventional medicaments such as MTX or other chemical DMARDs orbiologics such as TNF inhibitors are frequently not reducingsufficiently the symptoms of RA experienced by such individuals.Accordingly, there is a need for new medicaments which can be used aloneor in addition to known medicaments, e.g., in combination with astandard MTX therapy, or other chemical DMARDs, e.g., for patientssuffering from moderate, moderate-to-severe or severe rheumatoidarthritis.

Another problem associated with the use of biologics (biotechnologicallyproduced active ingredients in a medicine), in particular biologics thatare not species-specific, for example chimeric antibodies ormouse-derived antibodies used in humans is the triggering of an immunereaction against the active ingredient that is recognized as annon-self/foreign antigen. It is therefore necessary to providemedicaments that do not induce immune reactions (e.g. anti-drugantibodies, ADA) against biologics.

The above objectives are achieved by the compositions, the neutralizingantibodies or functional fragments thereof (also referred to as activeingredients) provided herein as well as by the methods of treatment ofRA symptoms using the herein provided compositions and activeingredients.

Furthermore, the present invention relates to the treatment of pain.Pain can be caused by various different stimuli such as burns, cuts orby diseases, e.g. cancer, chronic diseases such as diverse inflammatorydiseases or acute diseases, e.g. headache. The treatment of pain dependson the pain intensity. The WHO introduced the term “pain ladder” in itsguideline for the use of drugs in the management of pain. Originallyapplied to the management of cancer pain, medical professionals use itas guidance in the treatment of different types of pain. According tothe recommendations of the WHO patients not suffering from severe painshould first be treated with non-opioid drugs such as paracetamol,non-steroidal anti-inflammatory drugs (NSAIDs) or COX-2 inhibitors. Whenpain persists despite treatment with the first line medicaments mildopioids such as codeine, tramadol-hydrochloride and the like may beused. Patients suffering from severe pain or agonizing pain respondgenerally well to treatment with opioids, such as morphine and the likeat the cost of side effects, which may become intolerable.

There is an ongoing need for the development of new analgesics, e.g.,analgesics that are not associated with uncontrollable side effects orwith side effects making their use completely intolerable, such assevere nausea, vomiting, gastrointestinal problems, dizziness, etc.Today, the most frequently prescribed analgesics are small organicmolecules. However, modern biotechnology and the understanding ofbiological mechanisms underlying pain and the detection of effectormolecules, surface receptors, etc. involved in the development andmaintenance of pain opened up the possibility of designing molecules,e.g. peptides or nucleic acids, specifically targeting such molecules.For example, it may be possible to provide small interfering RNA (siRNA)molecules that switch off genes involved in the pain transmission, e.g.genes encoding nociceptors on cell surfaces. Another alternative wouldbe to target proteins that are directly involved in the development orconductance of pain, e.g. nociceptors or down-stream molecules expressedon the surface or inside neuronal cells (cf. e.g. Stosser et al., J MolMed (2011) 89:321-329).

Recently, receptors for factors that were originally discovered asimportant for the immune system or for hemostasis have been identifiedon the surface of peripheral neuronal cells. WO2010/071923 discloses thedevelopment of antibodies binding rodent GM-CSF and their use in animalmodels of pain. Antibodies directed to primate, e.g. human, GM-CSF werenot tested.

Originally described as a potent stimulus of the growth anddifferentiation of granulocyte and macrophage precursor cells in vitro,granulocyte-macrophage colony-stimulating factor (GM-CSF) is anapproximately 23 kDa glycoprotein with a four alpha helical bundlestructure that binds to a heterodimeric receptor composed of subunitsbelonging to the type 1 cytokine receptor family. It stimulates thematuration of, i.a., macrophages, neutrophils, granulocytes, eosinophilsand antigen-presenting dendritic cells, to increase their functionalcapacity in combating infections. Genetic ablation experiments i.e.experiments silencing or knocking out the gene of interest—hereGM-CSF—in mice indicated that GM-CSF is essential for maintaining thefunctional activity of some macrophage populations such as thoseinvolved in clearing surfactant in the lung and in responding to certainkinds of infection or immune responses.

GM-CSF has potent stimulatory activities in vitro on progenitor cellsfor neutrophils, eosinophils, macrophages, and to a lesser extenterythroid and megakaryocyte cells. Results obtained in vivo with geneknockout mice suggest that the major physiological role of GM-CSF is tomaintain or stimulate the functional activity of mature macrophages andgranulocytes and to stimulate antigen presentation to the immune system.It does the latter by its direct effects on dendritic cell andmacrophage production, but also by increasing, expression of the classII major histocompatibility complex and Fc receptors on macrophages anddendritic cells.

GM-CSF stimulates the functional activities of neutrophils, eosinophils,and monocyte-macrophages. These include enhancement of chemotacticactivity, increased expression of cellular adhesion molecules andincreased adhesion to surfaces, and increased phagocytic activity aswell as inhibition and delay of apoptosis of these cells. Neutrophilsrepresent the first line of defense against aggressions. The programmeddeath of neutrophils is delayed by proinflammatory stimuli includingGM-CSF to ensure a proper resolution of the inflammation in time andplace. GM-CSF also stimulates the capacity of these cells to mediateantibody-dependent cell cytotoxicity and to kill microorganismsintracellularly and has a ‘priming’ effect on these cells to enhancetheir response to subsequent stimuli for the oxidative burst (superoxideanion production), degranulation and release of antimicrobial agents,and chemotaxis. Further, GM-CSF stimulates the release of secondarycytokines and mediators from these cells including IL-1, G-CSF, M-CSF,and leukotrienes from neutrophils, as well as IL-1, TNF, IL-6, G-CSF,M-CSF, and prostaglandins from macrophages.

It is clear from the above that GM-CSF plays a key role in activatingand maintaining the cell populations necessary to ward off infection.However, in some instances activation of these cell populations may beundesirable. For example, activation of the above cell lineages when nopathogen is present leads in many instances to acute and/or chronicinflammatory conditions which, in extreme cases, may belife-threatening. Similarly, treatment with or over-expression of GM-CSFmay lead to excess immune activation and this may be accompanied bypain. The role of pain in RA is discussed, e.g., in David Walsh andDaniel McWilliams, Curr Pain Headache Rep (2012) 16:509-517. In suchinstances, it may be desirable to neutralize the activity of GM-CSF suchthat the pain is reduced or eliminated.

Further, it has been shown that administration of GM-CSF to animalssuffering from experimentally induced diseases (e.g. collagen-inducedarthritis, etc.; cf. e.g. Bischof, R. J. et al. Clin Exp Immunol., 2000February; 119(2): 361-367) or to patients afflicted with diseases, suchas Felty's syndrome, may worsen disease symptoms (Hazenberg B P C, etal.; Blood, 1989; 83:876-82) and cause painful sensations. GM-CSFreceptors are expressed on peripheral nerve cells, for example onnociceptive neurons. Accordingly, neutralization or antagonizing theactivities of GM-CSF may prevent the stimulus of GM-CSF exerted on suchneuronal cells. Blocking nociception is an aim in many differentpathologic conditions or diseases which are very painful. Thus, theadministration of pharmaceuticals comprising GM-CSF antagonists may bean effective way to substitute or complement commonly used paintreatment.

It is therefore an aim of the invention to provide neutralizingantibodies and functional fragments thereof targeting GM-CSF, analgesiccompositions comprising the same, and uses thereof comprising to reducepainful sensations in subjects, e.g., human patients, particularly inhuman patients suffering from rheumatoid arthritis or other autoimmuneor muscoloskeletal disorders, cancer, neurodegenerative diseases,wounds, burns, etc.

It is another objective of the invention to provide neutralizingantibodies and functional fragments thereof targeting GM-CSF, analgesiccompositions comprising the same that can be used in methods oftreatment of human patients suffering from RA, which are insufficientlycontrollable with methotrexate (MTX) alone, with DMARDs, MTX plus otherchemical DMARD(s) or one TNF inhibitor. These neutralizing antibodiesand functional fragments thereof targeting GM-CSF or analgesiccompositions comprising the same are conventionally used in thetreatment of RA patients, but are sometimes insufficient to reduce thedisease symptoms, e.g. pain, or lead to a remission of disease.Accordingly, there is a need for drugs that are effective in reducingdisease activity, e.g. as can be determined using the DAS28CRP clinicalassessment, thereby also reducing pain associated with the underlyingdisease, e.g. RA. It is one objective of the present invention toprovide such neutralizing antibodies and functional fragments thereoftargeting GM-CSF, analgesic compositions comprising the same.

Other objectives of the present invention are:

-   -   An improvement of the general physical function in a treated        individual; and/or    -   Preventing or reducing fatigue in patients treated with the        compositions of the invention; and/or    -   Preventing or reducing fatigue in patients treated with the        analgesic compositions of the invention; and/or    -   Improving the quality of life of the patient; and/or    -   Improving work productivity; and/or    -   Improving safety and tolerability of the medicament; and/or    -   Improving immunogenicity (e.g. prevention or minimization of the        formation of anti-drug antibodies (ADA), e.g. neutralizing        antibodies, against the active ingredients of the inventive        medicaments.

An additional problem in the treatment of RA patients is thatconventional medicaments such as DMARDs, e.g. anti-folate compounds suchas MTX, alone or in combination with other chemical or biologic such asTNF inhibitors are not to alleviating sufficiently pain experienced bysuch individuals. Accordingly, there is a need for new medicaments whichcan be used alone or in addition to known medicaments, e.g., incombination with a standard MTX therapy or other chemical DMARDs, or anMTX therapy and the additional administration of one or more otherchemical DMARDs, e.g., for patients suffering from moderate-to-severerheumatoid arthritis.

Another problem associated with the use of biologics, in particularbiologics that are not species specific, for example chimeric antibodiesor mouse-derived antibodies used in humans is their potentialimmunogenicity. It is therefore necessary to provide medicaments thatinduce very rarely immune reactions (e.g. anti-drug antibodies, ADA)against biologics.

The above objectives are achieved by the neutralizing antibodies andfunctional fragments thereof targeting GM-CSF, analgesic compositionscomprising the same (also referred to as active ingredients) providedherein as well as by the methods of treatment of pain using the hereinprovided analgesics and active ingredients.

It must be noted that as used herein, the singular forms “a”, “an”, and“the”, include plural references unless the context clearly indicatesotherwise. Thus, for example, reference to “an antibody” includes one ormore of such different antibodies and reference to “the method” includesreference to equivalent steps and methods known to those of ordinaryskill in the art that could be modified or substituted for the methodsdescribed herein.

Unless otherwise indicated, the term “at least” preceding a series ofelements is to be understood to refer to every element in the series.Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the present invention.

Throughout this specification and the claims which follow, unless thecontext requires otherwise, the word “comprise”, and variations such as“comprises” and “comprising”, will be understood to imply the inclusionof a stated integer or step or group of integers or steps but not theexclusion of any other integer or step or group of integer or step. Whenused herein the term “comprising” can be substituted with the term“containing” or sometimes when used herein with the term “having” orcould even be replaced by consisting of.

As used herein, the conjunctive term “and/or” between multiple recitedelements is understood as encompassing both individual and combinedoptions. For instance, where two elements are conjoined by “and/or”, afirst option refers to the applicability of the first element withoutthe second. A second option refers to the applicability of the secondelement without the first. A third option refers to the applicability ofthe first and second elements together. Any one of these options isunderstood to fall within the meaning, and therefore satisfy therequirement of the term “and/or” as used herein. Concurrentapplicability of more than one of the options is also understood to fallwithin the meaning, and therefore satisfy the requirement of the term“and/or” as used herein.

Several documents are cited throughout the text of this specification.Each of the documents cited herein (including all patents, patentapplications, scientific publications, manufacturer's specifications,instructions, etc.), whether supra or infra, are hereby incorporated byreference in their entirety. To the extent the material incorporated byreference contradicts or is inconsistent with this specification, thespecification will supersede any such material. Nothing herein is to beconstrued as an admission that the invention is not entitled to antedatesuch disclosure by virtue of prior invention.

DESCRIPTION OF THE INVENTION

Aspects of the invention relate to a neutralizing antibody or afunctional fragment thereof specifically binding primate GM-CSF, whereinsaid antibody comprises a light chain variable region comprising anamino acid sequence as set out in SEQ ID NOs: 19, 34, 54 or 55, and aheavy chain variable region comprising an amino acid sequence chosenfrom the group consisting of those set out in any of the SEQ ID NOs:20-33, 35-48, 52 or 53. Any possible combination of sequences ofvariable region is explicitly encompassed by the scope of the presentinvention, e.g. combinations of SEQ ID NO: 19 and SEQ ID NO: 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, or 33, and combinations of theremaining heavy and light chain variable regions is possible.

The invention also relates to a neutralizing antibody or a functionalfragment thereof specifically binding primate GM-CSF or an analgesiccomposition comprising such, wherein said antibody comprises a lightchain variable region comprising an amino acid sequence as set out inSEQ ID NOs: 19, 34, 54 or 55, and a heavy chain variable regioncomprising an amino acid sequence chosen from the group consisting ofthose set out in any of the SEQ ID NOs: 20-33, 35-48, 52 or 53. Anypossible combination of sequences of variable region is explicitlyencompassed by the scope of the present invention, e.g. combinations ofSEQ ID NO: 19 and SEQ ID NO: 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,31, 32, or 33, and combinations of the remaining heavy and light chainvariable regions is possible. The production of the neutralizingantibodies and functional fragments discussed herein is disclosed indetail in WO 2006/111353, the contents of which are disclosed herein intheir entirety. With respect to the sequences, reference is made to thesequence listing in said publication. Sequence identity numbers thereincorrespond to sequence identity numbers in the present application.

In accordance with the invention, the neutralizing antibody or afunctional fragment thereof specifically binding primate GM-CSF havingin its heavy chain variable region a CDR3 comprising an amino acidsequence chosen from the group consisting of those set out in any of theSEQ ID NOs: 1-13 or 56.

Further, according to the invention, the neutralizing antibodies andfunctional fragments thereof targeting GM-CSF, the analgesiccompositions comprising the same comprise in their heavy chain variableregion a CDR3 comprising an amino acid sequence chosen from the groupconsisting of those set out in any of the SEQ ID NOs: 1-13 or 56.

In accordance with the invention, the neutralizing antibody orfunctional fragment thereof comprising a heavy chain variable regionCDR3 sequence set out in any of the amino acid sequences in SEQ ID NOs:1-13 or 56 together with the heavy chain variable region CDR1 sequenceset out in the amino acid sequence of SEQ ID NO: 14 and heavy chainvariable region CDR2 sequence set out in the amino acid sequence of SEQID NO: 15.

According to the invention, the neutralizing antibodies and functionalfragments thereof targeting GM-CSF, the analgesic compositionscomprising the same comprise in their heavy chain a variable region CDR3sequence set out in any of the amino acid sequences in SEQ ID NOs: 1-13or 56 together with the heavy chain variable region CDR1 sequence setout in the amino acid sequence of SEQ ID NO: 14 and heavy chain variableregion CDR2 sequence set out in the amino acid sequence of SEQ ID NO:15.

In accordance with the invention, the neutralizing antibody orfunctional fragment thereof having in its light chain variable region aCDR1 comprising the amino acid sequence set out in SEQ ID NO: 16, a CDR2comprising the amino acid sequence set out in SEQ ID NO: 17, and a CDR3comprising the amino acid sequence set out in SEQ ID NO: 18.

According to the invention, the neutralizing antibodies and functionalfragments thereof targeting GM-CSF, the analgesic compositionscomprising the same comprise in their light chain variable region a CDR1comprising the amino acid sequence set out in SEQ ID NO: 16, a CDR2comprising the amino acid sequence set out in SEQ ID NO: 17, and a CDR3comprising the amino acid sequence set out in SEQ ID NO: 18.

In accordance with the invention, the neutralizing antibody orfunctional fragment thereof having in its light chain variable region aCDR1 comprising an amino acid sequence as set out in SEQ ID NO: 16, aCDR2 having an amino acid sequence as set out in SEQ ID NO: 17 and aCDR3 having an amino acid sequence as set out in SEQ ID NO: 18; andcomprising in its heavy chain variable region a CDR1 region comprisingan amino acid sequence as set out in SEQ ID NO: 14, a CDR2 region havingan amino acid sequence as set out in SEQ ID NO: 15 and a CDR3 having anamino acid sequence as set out in any of SEQ ID Nos: 1-13 or 56.

According to the invention, the neutralizing antibodies and functionalfragments thereof targeting GM-CSF, the analgesic compositionscomprising the same comprise in their light chain variable region a CDR1comprising an amino acid sequence as set out in SEQ ID NO: 16, a CDR2having an amino acid sequence as set out in SEQ ID NO: 17 and a CDR3having an amino acid sequence as set out in SEQ ID NO: 18; andcomprising in their heavy chain variable region a CDR1 region comprisingan amino acid sequence as set out in SEQ ID NO: 14, a CDR2 region havingan amino acid sequence as set out in SEQ ID NO: 15 and a CDR3 having anamino acid sequence as set out in any of SEQ ID Nos: 1-13 or 56.

In a preferred embodiment, the neutralizing antibodies and functionalfragments thereof targeting GM-CSF, the analgesic compositionscomprising the same comprise in their light chain variable region a CDR1comprising an amino acid sequence as set out in SEQ ID NO: 16, a CDR2having an amino acid sequence as set out in SEQ ID NO: 17 and a CDR3having an amino acid sequence as set out in SEQ ID NO: 18; andcomprising in their heavy chain variable region a CDR1 region comprisingan amino acid sequence as set out in SEQ ID NO: 14, a CDR2 region havingan amino acid sequence as set out in SEQ ID NO: 15 and a CDR3 having anamino acid sequence as set out in SEQ ID NO: 2.

In accordance with the invention, the neutralizing antibody or afunctional fragment thereof specifically binding primate GM-CSFcomprises a light chain amino acid sequence as set out in SEQ ID NO: 34and a heavy chain amino acid sequence as set out in any of SEQ ID NOs:35-48.

According to the invention, the neutralizing antibodies and functionalfragments thereof targeting GM-CSF, or the analgesic compositionscomprising the same comprise in their light chain amino acid sequence asset out in SEQ ID NO: 34 and a heavy chain amino acid sequence as setout in any of SEQ ID NOs: 35-48.

In a further preferred embodiment, the neutralizing antibodies andfunctional fragments thereof targeting GM-CSF, or the analgesiccompositions comprising the same comprise in their light chain aminoacid sequence as set out in SEQ ID NO: 34 and a heavy chain amino acidsequence as set out in SEQ ID NO: 35.

In accordance with the invention, the neutralizing antibody or afunctional fragment thereof specifically binding primate GM-CSFcomprises an amino acid sequence bearing at least 70%, at least 75%, atleast 80%, at least 85%, at least 90%, at least 95%, at least 97%, or atleast 99% homology to the to the respective amino acid sequence as setout in any of SEQ ID NOs: 1-48 and/or 52-56.

According to the invention, the neutralizing antibodies and functionalfragments thereof targeting GM-CSF, the analgesic compositionscomprising the same comprise an amino acid sequence bearing at least70%, at least 75%, at least 80%, at least 85%, at least 90%, at least95%, at least 97%, or at least 99% identity to the respective amino acidsequence as set out in any of SEQ ID NOs: 1-48 and/or 52-56.

In accordance with the invention, neutralizing anti-primate GM-CSFantibody or functional fragment thereof as described above for use inthe treatment of RA symptoms in a subject are provided. Preferably, thesubject is a mammal, more preferably a human patient. In other preferredembodiments, the neutralizing anti-primate GM-CSF antibody or functionalfragment thereof for use in the treatment of RA symptoms in a subjectaccording to the present invention is used together (e.g. at the sametime or one before or after the other, according to the prescriptionregulations of respective drugs; e.g. before or after a meal) with atleast one further active ingredient of a medicament.

According to the invention, neutralizing anti-primate GM-CSF antibody orfunctional fragment thereof as described above for use in the treatmentof pain in a subject are provided. In preferred embodiments, the subjectis a mammal, e.g., a human. In other preferred embodiments, theneutralizing anti-primate GM-CSF antibody or functional fragment thereoffor use in the treatment of pain in a subject according to the presentinvention is used together (e.g. at the same time or one before or afterthe other, according to the prescription regulations of respectivedrugs, e.g. before or after a meal) with at least one further analgesiccompound.

According to the invention, the neutralizing anti-primate GM-CSFantibody or functional fragment for use according to the presentinvention or any of the compositions described above, which comprise theneutralizing anti-primate GM-CSF antibody or functional fragment thereofis formulated for subcutaneous administration. This means, that theformulation has a viscosity that allows for subcutaneous injection andthat the concentration of active ingredient is sufficiently high toinject a therapeutically effective dose using one injection peradministered dose in order to take into account patient compliance.

According to the invention, the neutralizing anti-primate GM-CSFantibody or functional fragment for use according to the presentinvention or any of the analgesic compositions described above, whichcomprise the neutralizing anti-primate GM-CSF antibody or functionalfragment thereof is formulated for subcutaneous administration. Thismeans, that the formulation has a viscosity that allows for subcutaneousinjection and that the concentration of active ingredient issufficiently high to inject a therapeutically effective dose using oneinjection per administered dose in order to take into account patientcompliance.

According to the invention, the neutralizing anti-primate GM-CSFantibody or functional fragment thereof for use according to the presentinvention is administered in combination with compounds selected frommethotrexate, corticosteroids (e.g. prednisolone), opioids (e.g.codeine), hydroxychloroquine (> or equal to 200 mg/day, or >400 mg/day),oral chloroquine (>250 mg/day), or other non-biologics DMARDs.

Further, according to the invention, the neutralizing anti-primateGM-CSF antibody or functional fragment thereof for use according to thepresent invention is used in combination with methotrexate or othernon-biologics DMARDs. Additional administration of oral corticosteroids(e.g. prednisolone or equivalents thereof) in doses up to 10 mg/day isalso contemplated. According to the invention, the treatment withopioide-containing medicines is also contemplated.

Further, according to the invention, the neutralizing anti-primateGM-CSF antibody or functional fragment thereof for use according to thepresent invention is administered in combination with compounds selectedfrom methotrexate, corticosteroids (e.g. prednisolone), opioids (e.g.codeine), DMARDs, hydroxychloroquine (> or equal to 200 mg/day, or >400mg/day), oral chloroquine (>250 mg/day), or optionally other biologics,e.g. therapeutic antibodies such as infliximab or other TNF-inhibitors,CD20-antagonists, IL-17-antagonists, or IL-6R inhibitors such astocilizumab.

In accordance with the present invention, the neutralizing anti-primateGM-CSF antibody or functional fragment thereof is used as activeingredient formulated for subcutaneous administration of doses of 10 mg,20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg,120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg,225 mg, 250 mg, 275 mg, or 300 mg per dose. These doses may beadministered once weekly, or in shorter or longer intervals, e.g. everysecond day, every third day, every fifth day, etc., or every second orthird week or monthly. The doses may be administered over a period ofseveral weeks or months according to the patients' specific needs. Forexample, administration over at least 3 weeks, 6 weeks, 12 weeks, 24weeks or longer is contemplated. The doses may increase over time, e.g.starting with a lower dose at the first injection (e.g. at least 20, 25,or 50 mg in a single or more doses), and increasing the dose in thefollowing injections, e.g. 50 to 100 mg, e.g. 75 or 80 mg at the secondinjection, and about 100 to 250 mg, e.g. 125 to 200 mg, e.g., about 150mg at the third injection.

In accordance with the present invention, it is possible that the dosesmay decrease over time, e.g. starting with a higher dose, called loadingdose, at the first injection (e.g. at least 150 or 300 mg in a single ormore doses), and decreasing the dose in the following injections, e.g.100 to 250 mg, e.g. 125 to 200 mg, e.g., about 150 mg at the secondinjection, 100 to 150 mg, e.g. 75 or 80 mg at the third injection.

In accordance with the present invention, it is possible to administerthese doses in more than one injection, but it is preferred that oneinjection is administered for patient compliance. Preferably, the dosesof the neutralizing anti-primate GM-CSF antibody or functional fragmentthereof remain the same, e.g. about 20 mg doses, optionally administeredas a first initial dose on day 1, then as a second dose about 14 daysafter the first initial dose, and then as further doses about every 28day. Further, preferably, the doses are the same, e.g. about 80 mgdoses, optionally administered on day 1, day 14, and then every 28 days.Further, the doses may be the same, e.g. about 150 mg doses, optionallyadministered on day 1, day 14, and then every 28 days. In a furtherembodiment, the doses are the same, e.g. about 20 mg, or about 80 mgdoses or about 150 mg doses, administered after day 1, day 28, and thenevery 28 days, that means in 4 weeks intervals.

In further embodiments of the embodiments referred to in the precedingsections, a so-called “loading dose” is administered about 7-21 days,e.g. 10-18 days, preferably 14 days before the administration of theabove described first dose. In preferred embodiments the loading dose isadministered 14 days before the first dose and comprises the same, ortwo times the amount of the subsequent dose. For example, when the firstinitial dose comprises 150 mg of the herein described neutralizingantibody or a fragment thereof, the loading dose is two times 150 mg.Optionally, the loading dose may be higher, e.g., three times the amountof the first dose. The loading dose may be administered subcutaneously.The rationale behind administration of a loading dose to a patient inneed thereof is that a steady state will be reached much quicker.

The second dose (ii) of the neutralizing antibody or a fragment thereofof the dosage regimen described herein may be administered 7-21 daysafter administration of the first initial dose, optionally 10-15 daysafter administration of the first initial dose. In one embodiment, thesecond dose is administered on day 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20 or 21 after administration of the first initial dose, inparticular on day 14 after administration of the first initial dose.

The second dose (ii) of the neutralizing antibody or a fragment thereofof the dosage regimen described herein may also be administered 21-35days after administration of the first initial dose, optionally 25-20days after administration of the first initial dose. In one embodiment,the second dose is administered on day 21, 22, 23, 24, 25, 26, 27, 28,29, 30, 31, 32, 33, 34, or 35 after administration of first initialdose, in particular on day 28 after administration of the first initialdose.

In very preferred embodiments, the neutralizing anti-primate GM-CSFantibody or functional fragment thereof for use according to the presentinvention is used in combination with methotrexate at conventionallyprescribed doses (e.g. maximally 25 mg/weekly, e.g., 7.5 mg to 25mg/weekly, most preferred 15 mg to 25 mg/week) or other non-biologicDMARDs.

In accordance with the invention, the neutralizing anti-primate GM-CSFantibody or functional fragment for use according to the presentinvention or any of the compositions comprising the neutralizinganti-primate GM-CSF antibody or functional fragment thereof isformulated for subcutaneous administration. This means, that theformulation has a viscosity that allows subcutaneous injection andfurther requires that the concentration of active ingredient issufficiently high to inject a therapeutically effective dose using oneinjection per administered dose taking into account patient compliance.

The further doses (d) may be administered to the patient as long he isin need of a treatment and/or prevention of RA or pain, or any otherarthritic or painful conditions referred to herein. Thus, the furtherdoses (d) may be administered to the patient until a full or partialremission or alleviation of symptoms of the disease as described herein,a reduction of, e.g., the DAS28-CRP score (see below) or reduction ofVAS pain (infra) is achieved. For example, further doses (d) may beadministered to the patient over a period of at least 2, at least 3, atleast 4, at least 5, at least 6, at least 7, at least 8, at least 9, atleast 10 weeks, at least 12 weeks, at least 15 weeks, at least 18 weeks,at least 21 weeks, at least 24 weeks, at least 30 weeks, at least 36weeks or over a period of at least 48 weeks, for at least 1 year, orlonger.

If the neutralizing antibody or a fragment thereof is used for theprevention of RA or is used as analgesic, further doses (d) may beadministered to the patient to the patient as long as full or partialprevention of these indications or related symptoms is desired.

It is to be understood that the administration of the neutralizingantibody or a fragment thereof may also be stopped after a certainperiod of treatment with the neutralizing antibody or fragment thereofafter which the desired effects (such as a reduction of the DAS28-CRPscore or VAS pain) have been achieved. This is due to the fact that thetherapeutic or preventive effects of the antibody or fragment thereofcan persist for a certain period of time after the administration hasbeen stopped. Such a “drug holiday” (or “drug vacation”, “medicationvacation”, “structured treatment interruption” or “strategic treatmentinterruption”) may reduce the risk of adverse (i.e. treatment-related)effects and may maintain the sensitivity to the neutralizing antibody orfragment thereof, may lead to the recovery of some normal physiologicfunctions in the patient or may improve patient compliance.

The time point for a drug holiday may vary from patient to patient andmay be chosen on the basis of the clinical assessment by the treatingphysician. This clinical assessment may take into account the presenceand desired extent of therapeutic effects achieved by administration ofthe neutralizing antibody or fragment thereof. Any effect defined hereinwith respect to the term “treatment” may be indicative that a drugholiday may be made.

In one embodiment of the invention, a drug holiday is made when thepatient shows a substantial reduction of the initial DAS28-CRP score.Disease severity is usually defined by the EULAR response criterion onthe basis of the DAS28.

DAS28 is the Disease Activity Score in which 28 joints in the body areassessed to determine the number of tender joints and the number ofswollen joints. When the DAS28 calculation includes a measurement ofC-reactive protein (CRP) rather than erythrocyte sedimentation rate(ESR), it is referred to as DAS28-CRP. CRP is believed to be a moredirect measure of inflammation than ESR, and is more sensitive to shortterm changes. CRP production is associated with radiological progressionin RA and is considered at least as valid as ESR to measure RA diseaseactivity.

DAS28-CRP>5.1 indicates severe disease activity. Moderate diseaseactivity is characterized by a DAS28-CRP of >3.2 and 5.1. Low diseaseactivity is characterized by a DAS28-CRP of <3.2. A DAS28-CRP of lessthan 2.6 indicates disease remission. Therefore, when a substantialimprovement of this parameter is achieved, e.g. low disease activity ordisease remission is achieved, a drug holiday may start. Alternatively,when a patient was initially diagnosed as suffering from severe disease,the drug holiday may be contemplated when such patient, after treatmentaccording to the invention, attains a low disease level or remission.

In another embodiment, a drug holiday may be made at least 6 months, atleast 7 months, at least 8 months, at least 9 months, at least 10months, at least 11 months or at least 12 months after administration ofthe first (or loading) dose (a). In yet another embodiment, a drugholiday may be made at least 6 months, at least 7 months, at least 8months, at least 9 months, at least 10 months, at least 11 months or atleast 12 months after administration of the second dose (b). In apreferred embodiment a drug holiday is made after a minimum treatment of6 months according to any of the methods disclosed herein.

During the drug holiday clinical parameters of the patient (such as theDAS28-CRP) are monitored in regular intervals, such as monthly. If theclinical parameters worsen, e.g. if the DAS28-CRP increases, theneutralizing antibody or a fragment thereof should again be administeredto the patient. In one embodiment such a worsening of the clinicalparameters may be an increase of the DAS28-CRP measured at the beginningof the drug holidays of about 25%, about 35%, about 45% or about 50% ormore, e.g. to a DAS28-CRP of >3.2, or in the case of disease remission,to a DAS28-CRP of more than 2.6, or even more than 3.2.

After a drug holiday, the neutralizing antibody or a fragment thereofmay again be used according to any the dosage regimen described herein.

According to the invention, methods of treatment of RA symptoms in asubject are provided, said methods comprising administering acomposition or neutralizing antibody or functional fragment thereofaccording to the invention and as defined above. In accordance with theinvention, the subject is a human subject, e.g. a human patient.

Further, in accordance with the present invention, methods of treatmentof pain in a subject are provided, said methods comprising administeringan analgesic composition or neutralizing antibody or functional fragmentthereof according to the invention and as defined above. In preferredembodiments, the subject is a human subject, e.g. a human patient.

According to the invention, methods of treatment of a subject sufferingfrom an autoimmune disease, e.g., rheumatoid arthritis are provided. Inaccordance with the invention, the methods of treatment in a subject areassociated with mild, mild to moderate, moderate, moderate to severe orsevere rheumatoid arthritis, e.g., moderate, moderate to severe orsevere rheumatoid arthritis. The classification used in the context ofthe present invention is based on the 2010 ACR/EULAR RheumatoidArthritis Classification Criteria (Arthritis & Rheumatism, Vol. 62, No.9, September 2010, pp. 2569-2581). These classification criteria,jointly published by the American College of Rheumatology (ACR) and theEuropean League Against Rheumatism (EULAR) establish a point valuebetween 0 and 10. Disease severity is usually defined by the value ofthe DAS28. DAS28-CRP>5.1 indicates severe disease activity. Moderatedisease activity is characterized by a DAS28-CRP of >3.2 and 5.1. Lowdisease activity is characterized by a DAS28-CRP of <3.2. A DAS28-CRP ofless than 2.6 indicates disease remission. When the DAS28 calculationincludes a measurement of C-reactive protein (CRP) rather thanerythrocyte sedimentation rate (ESR), it is referred to as DAS28-CRP.CRP is believed to be a more direct measure of inflammation than ESR,and is more sensitive to short term changes. CRP production isassociated with radiological progression in RA and is considered atleast as valid as ESR to measure RA disease activity. The methods of thepresent invention induce a disease remission or an amelioration below aDAS28-CRP value of <3.2, preferably of at least 1.2.

The clinical benefit of using the neutralizing antibody or functionalfragment thereof according to the invention may be an improvement of atleast 20%, at least 50% or at least 70% treatment efficacy as determinedby the 1987 ACR criteria, i.e. the clinical benefit may be achieving ACR20, ACR 50 or ACR 70, respectively. The clinical benefit comprisesachieving ACR 20 in at least 40, 50, 55, 60, 65 or 70% of patients. Itmay comprise achieving ACR 50 in at least 20%, 25%, 30%, 35% or at least40% of patients. It may comprise achieving ACR 70 in at least 5%, 10%,15% or 20% of patients with insufficiently controlled RA by MTX or othernon-biologic DMARDs treatment.

According to the present invention, the neutralizing antibody or afunctional fragment thereof specifically binding primate GM-CSF for usein the treatment of an inflammatory disease, e.g., RA, in a patient toprovide clinical benefit as measured by a decrease in DAS28-CRP by morethan 1.2 within 85 days, the method comprising administering acomposition comprising the neutralizing antibody to GM-CSF or afunctional fragment thereof to the patient, wherein the composition isadministered, e.g., at a dose of 20 mg or 50 mg or 80 mg or 150 mg/monthafter two initial injections of the same dose on day one and/or about 14days later by subcutaneous administration.

In accordance with the present invention, the neutralizing antibody or afunctional fragment thereof specifically binding primate GM-CSF for usein the treatment of an inflammatory disease, e.g., RA to provideclinical benefit as measured by an improvement of at least ACR20, atleast ACR50 or at least ACR70 within about 7 weeks, the methodcomprising administering a composition comprising the neutralizingantibody or functional fragment thereof to the patient, wherein thecomposition is administered at a dose of 20 mg or of 50 mg or of 80 mgor of 150 mg/month after two initial injections of the same dose on dayone and about 14 days later, e.g., by subcutaneous administration.Preferably, the therapeutic effect is detectable within preferably 2, 3or 4 weeks after treatment begin.

In accordance with the present invention, the neutralizing antibody or afunctional fragment thereof specifically binding primate GM-CSF for usein the treatment of an inflammatory disease, e.g., RA for inducingremission of RA in a patient, as measured by a DAS28-CRP of less than2.6, the method comprising administering a composition comprising atherapeutically effective amount of the neutralizing antibody orfunctional fragment thereof to the patient, wherein the composition isadministered by subcutaneous administration, and wherein the onset ofremission is seen after about 2 weeks, at least after 3 weeks, at leastafter 4 weeks, at least after 5 weeks, at least after 6 weeks, at leastafter 8 weeks, at least after 10 weeks, or at least 12 weeks after theinitial administration of the neutralizing antibody or functionalfragments thereof disclosed herein.

In accordance with the present invention, the neutralizing antibody or afunctional fragment thereof specifically binding primate GM-CSF for usein the treatment of an inflammatory disease, e.g., RA, resulting in animprovement of physical function of an RA patient, as determined byHAQ-DI, is used in a method comprising administering a compositioncomprising the neutralizing antibody or a functional fragment thereofspecifically binding GM-CSF to the patient, wherein the composition isadministered in a dose of 10-150 mg, e.g., at a dose of 10-30 mg, e.g.,20 mg, or at a dose of 50-150 mg, e.g., at a dose of 80 mg, or at a doseof 100-300 mg, e.g., at a dose of 150 mg, in 1 ml monthly bysubcutaneous administration, and wherein an improvement in HAQ-DI isachieved within about 2 weeks, at least after 3 weeks, at least after 4weeks, at least after 5 weeks, at least after 6 weeks, at least after 8weeks, at least after 10 weeks, or at least 12 weeks, e.g., wherein theimprovement is a reduction of at least 0.25 in the patient's HAQ-DIscore.

In accordance with the methods of the present invention, the treatmentalleviates fatigue and/or sleeping disturbances associated with pain (asdetermined using the Facit-Fatigue, the MOS sleep scale or any othersuitable scale).

In accordance with the invention, the methods of the present invention,the treatment alleviates fatigue and/or sleeping disturbances (asdetermined using the Facit-Fatigue, the MOS sleep scale or otherclassification systems for the assessment of sleeping disturbances).

In accordance with methods of the present invention, the administrationof a composition or neutralizing antibody or functional fragment thereofrarely or only minimally induces formation of anti-drug antibodies,neutralizing anti-drug antibodies, or increases of native anti-GM-CSFautoantibodies compared with the start of the treatment, and at leastdoes not to induce such antibodies to an extent where the treatment hasto be interrupted.

In accordance with the methods of the present invention, the treatmentof an inflammatory disease comprises the subcutaneous administration ofthe above-described compositions or neutralizing antibody or functionalfragment thereof. The compositions, or the neutralizing antibody orfunctional fragment s thereof of the present invention may beadministered subcutaneously in the inventive methods of treatment of aninflammatory disease, e.g. at doses of 10 mg, 20 mg, 30 mg, 40 mg, 50mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg,150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 225 mg, 250 mg, 275 mg,of 300 mg, or higher. It is contemplated that the compositions, or theneutralizing antibody or functional fragment s thereof of the presentinvention is administered subcutaneously at doses of 10 mg, 20 mg, 30mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg,130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 225 mg,250 mg, 275 mg, of 300 mg, in at least 3, e.g., at least 5, e.g., atleast 7 doses over a period of at least 21 weeks. It is, however,possible to administer fewer or more of doses according to the specificrequirements and the patient's characteristics (e.g. depending onseverity of disease, gender, age, weight, other drugs used, etc.). Theduration of the treatment may be at least 21 weeks, but it iscontemplated that the therapeutic methods of the invention are set forthas long as necessary. It is also contemplated that MTX is administeredat the same time according to standard therapeutic regimen (e.g. 7.5 mgto 25 mg MTX per week as suggested in the Guidelines of the BritishSociety for Rheumatology of July 2000), e.g., at a dose of 7.5 to 25mg/week, 15 to 25 mg/week or 7.5 to 15 mg/week.

It is also possible to administer the herein disclosed compositions, orof the neutralizing antibody or functional fragment s thereof for any ofthe above time periods, but with intervals, e g administer thecompositions or active ingredients for 2, 3, or 4 weeks or 1, 2, or 3months and use an interval of 2, 3, or 4 weeks or 1, 2, or 3 months,where no composition is administered. At the same time, administrationof MTX at the above indicated weekly doses should be continued,optionally accompanied by supplementary administration of folicacid/folinic acid on the days where MTX is not administered.

In accordance with the methods of the present invention, administrationof any of the herein disclosed compositions, or of the neutralizingantibody or functional fragment s thereof in a pharmaceuticallyacceptable carrier, e.g., in a pharmaceutically acceptable carrier thatallows for subcutaneous administration is contemplated. In accordancewith the methods of the present invention, administration of thecomposition or neutralizing antibody or functional fragment thereofresults in an about ≥20%, about ≥25%, about ≥30% ≥40%, or about ≥50%reduction of pain as measured on the 100 mm VAS scale after 12 weeks.

In accordance with the methods of the present invention, administrationof the composition or neutralizing antibody or functional fragmentthereof results in an in vivo half-life of the active ingredient ofabout 2 to 4 weeks, e.g. about 2 to 3 weeks after administration to thepatient.

Furthermore, it is also possible to use other biologics in combinationwith the compositions of the present invention, for example monoclonalantibodies targeting CD20, for example rituximab, or antibodiestargeting other cytokines or cytokine receptors, for exampletocilizumab, which targets the IL-6 receptor, or antibodies targetingthe GM-CSF-receptor.

The compositions or medicaments according to the invention comprisingthe above antibodies or functional fragments or uses thereof areembodiments of the invention.

Compositions or medicaments according to the invention or kitscomprising the above antibodies or functional fragments or uses thereofare embodiments of the invention.

The compositions or medicaments comprising the above antibodies orfunctional fragments or uses thereof are embodiments of the invention.

It is contemplated that the present methods and compositions may beemployed for the treatment of pain from chronic conditions (includinginhibiting progression of and/or reversing damage associated withchronic conditions). Chronic conditions include, for example, arthriticconditions such as osteoarthritis, rheumatoid arthritis, and psoriaticarthritis. For example, the present methods and compositions may be usedto treat one or more symptoms or signs of osteoarthritis of the joint,(such as a hip or knee) or the back (for example, the lower back).Chronic conditions also include, for example, conditions associated withor resulting from pain such as chronic pain, including pain associatedwith or arising from cancer, from infection or from the nervous system(e.g., neurogenic pain such as peripheral neurogenic pain followingpressure upon or stretching of a peripheral nerve or root or having itsorigin in stroke, multiple sclerosis or trauma, including of the spinalcord). Chronic conditions also include, for example, conditionsassociated with or arising from psychogenic pain (e.g., pain not due topast disease or injury or visible sign of damage inside or outside thenervous system). The present methods and compositions may also beemployed for the treatment of back pain from other arthritic conditions,including gout and spondylarthropathies (including ankylosingspondylitis, Reiter's syndrome, psoriatic arthropathy, enterapathricspondylitis, juvenile arthropathy or juvenile ankylosing spondylitis,and reactive arthropathy). The present methods and compositions may beused for the treatment of back pain from infectious or post-infectiousarthritis (including gonoccocal arthritis, tuberculous arthritis, viralarthritis, fungal arthritis, syphlitic arthritis, and Lyme disease).

The invention provides methods of treatment of pain in a subject,wherein the pain is associated with an autoimmune disease, e.g.,rheumatoid arthritis. In accordance with the invention, the methods oftreatment of pain in a subject are associated with mild, mild tomoderate, moderate, moderate to severe or severe rheumatoid arthritis,e.g., moderate, moderate to severe or severe rheumatoid arthritis. Theclassification used in the context of the present invention is based onthe 2010 ACR/EULAR Rheumatoid Arthritis Classification Criteria(Arthritis & Rheumatism, Vol. 62, No. 9, September 2010, pp. 2569-2581).These classification criteria, jointly published by the American Collegeof Rheumatology (ACR) and the European League Against Rheumatism (EULAR)establish a point value between 0 and 10. Disease severity is usuallydefined by the EULAR response criterion on the basis of the DAS28.DAS28-CRP>5.1 indicates severe disease activity. Moderate diseaseactivity is characterized by a DAS28-CRP of >3.2 and 5.1. Low diseaseactivity is characterized by a DAS28-CRP of ≤3.2. A DAS of less than 2.6indicates disease remission. DAS28-CRP between 2.6 and 3.2 indicates lowdisease activity. DAS28 is the Disease Activity Score in which 28 jointsin the body are assessed to determine the number of tender joints andthe number of swollen joints. When the DAS28 calculation includes ameasurement of C-reactive protein (CRP) rather than erythrocytesedimentation rate (ESR), it is referred to as DAS28-CRP. CRP isbelieved to be a more direct measure of inflammation than ESR, and ismore sensitive to short term changes. CRP production is associated withradiological progression in RA and is considered at least as valid asESR to measure RA disease activity. The methods of the present inventioninduce a disease remission or an amelioration below a DAS28-CRP value of<3.2.

Aspects of the Invention

-   -   1. A neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        pain emanating from an inflammatory disease selected from a        group comprising rheumatoid arthritis, systemic lupus        erythematosus (SLE), psoriatic arthritis, ankylosing        spondylitis, juvenile idiopathic arthritis, and osteoarthritis,        -   wherein the neutralizing antibody or a functional fragment            specifically binding primate GM-CSF is used according to the            following dosing scheme:            -   (i) a first initial dose,            -   (ii) followed by administration of a second dose within                a period of 7-21 days after said first initial dose,            -   (iii) at least one further dose administered within a                period of 21-35 days after said second dose,            -   (iv) optionally followed by further doses administered                within intervals of 21-35 days.    -   2. The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        pain emanating from an inflammatory disease according to item 1,        wherein said disease is selected from a group comprising        rheumatoid arthritis, SLE, psoriatic arthritis, ankylosing        spondylitis, juvenile idiopathic arthritis and osteoarthritis,        -   wherein the neutralizing antibody or a functional fragment            specifically binding primate GM-CSF is used according to the            following dosing scheme:            -   (i) a first initial dose,            -   (ii) followed by administration of a second dose after                about 14 days after the first initial dose,            -   (iii) at least one further dose administered after about                28 days after said second dose,            -   (iv) optionally followed by further doses administered                within intervals of about 28 days.    -   3. The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        pain emanating from an inflammatory disease according to items 1        or 2, wherein said disease is selected from a group comprising        rheumatoid arthritis, SLE, psoriatic arthritis, ankylosing        spondylitis, juvenile idiopathic arthritis and osteoarthritis,        -   wherein the neutralizing antibody or a functional fragment            specifically binding primate GM-CSF is used according to the            following dosing scheme:            -   (i) a first initial dose,            -   (ii) followed by administration of a second dose after                about 14 days after the first initial dose,            -   (iii) at least one further dose administered after about                28 days after said second dose,            -   (iv) optionally followed by further doses administered                within intervals of about 28 days, and        -   wherein the patients receive at least one additional            anti-inflammatory drug selected from the group comprising            DMARDs, corticosteroids, e.g. glucocorticoids, NSAIDS,            opioids, and biologic drugs.    -   4. The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        pain emanating from an inflammatory disease according to items 1        to 3, wherein said disease is selected from a group comprising        rheumatoid arthritis, SLE, psoriatic arthritis, ankylosing        spondylitis, juvenile idiopathic arthritis and osteoarthritis,        -   wherein the neutralizing antibody or a functional fragment            specifically binding primate GM-CSF is used according to the            following dosing scheme:            -   (i) a first initial dose,            -   (ii) followed by administration of a second dose after                about 14 days after the first initial dose,            -   (iii) at least one further dose administered after about                28 days after said second dose,            -   (iv) optionally followed by further doses administered                within intervals of about 28 days, and        -   wherein the at least one additional anti-inflammatory drug            is selected from anti-folate compounds.    -   5. The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        pain emanating from an inflammatory disease according to items 1        to 4, wherein said disease is selected from a group comprising        rheumatoid arthritis, SLE, psoriatic arthritis, ankylosing        spondylitis, juvenile idiopathic arthritis and osteoarthritis,        -   wherein the neutralizing antibody or a functional fragment            specifically binding primate GM-CSF is used according to the            following dosing scheme:            -   (i) a first initial dose,            -   (ii) followed by administration of a second dose after                about 14 days after the first initial dose,            -   (iii) at least one further dose administered after about                28 days after said second dose,            -   (iv) optionally followed by further doses administered                within intervals of about 28 days, and        -   wherein the anti-folate compound is methotrexate.    -   6. The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        pain emanating from an inflammatory disease according to items 1        to 5, wherein said disease is selected from a group comprising        rheumatoid arthritis, SLE, psoriatic arthritis, ankylosing        spondylitis, juvenile idiopathic arthritis and osteoarthritis,        -   wherein the neutralizing antibody or a functional fragment            specifically binding primate GM-CSF is used according to the            following dosing scheme:            -   (i) a first initial dose,            -   (ii) followed by administration of a second dose after                about 14 days after the first initial dose,            -   (iii) at least one further dose administered after about                28 days after said second dose,            -   (iv) optionally followed by further doses administered                within intervals of about 28 days, and        -   wherein the methotrexate is administered once weekly.    -   7. The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        pain emanating from an inflammatory disease according to items 1        to 6, wherein said disease is selected from a group comprising        rheumatoid arthritis, SLE, psoriatic arthritis, ankylosing        spondylitis, juvenile idiopathic arthritis and osteoarthritis,        -   wherein the neutralizing antibody or a functional fragment            specifically binding primate GM-CSF is used according to the            following dosing scheme:            -   (i) a first initial dose,            -   (ii) followed by administration of a second dose after                about 14 days after the first initial dose,            -   (iii) at least one further dose administered after about                28 days after said second dose,            -   (iv) optionally followed by further doses administered                within intervals of about 28 days, and        -   wherein the at least one additional anti-inflammatory drug            is methotrexate that is administered at weekly doses, e.g.            once a week, at a dose per administration of 7.5 to 25 mg,            e.g., 15-25 mg, or 7.5 to 15 mg.    -   8. The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        pain emanating from an inflammatory disease according to items 1        to 7, wherein said disease is selected from a group comprising        rheumatoid arthritis, SLE, psoriatic arthritis, ankylosing        spondylitis, juvenile idiopathic arthritis and osteoarthritis,        -   wherein the neutralizing antibody or a functional fragment            specifically binding primate GM-CSF is used according to the            following dosing scheme:            -   (i) a first initial dose,            -   (ii) followed by administration of a second dose after                about 14 days after the first initial dose,            -   (iii) at least one further dose administered after about                28 days after said second dose,            -   (iv) optionally followed by further doses administered                within intervals of about 28 days, and        -   wherein the antibody is formulated for subcutaneous            administration.    -   9. A neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        pain emanating from an inflammatory disease selected from a        group comprising rheumatoid arthritis, ankylosing spondylitis,        juvenile idiopathic arthritis SLE, psoriatic arthritis, and        osteoarthritis,        -   wherein said disease is wherein the neutralizing antibody or            a functional fragment thereof specifically binding primate            GM-CSF is used according to the following dosing scheme:            -   (i) a first initial dose,            -   (ii) followed by administration of a second dose within                a period of 7-21 days after the first initial dose,            -   (iii) at least one further dose administered within a                period of 21-35 days after said second dose,            -   (iv) optionally followed by further doses administered                within intervals of 21-35 days,        -   wherein the patients are selected from the following patient            subgroups:            -   a-1) Patients previously not treated for an inflammatory                disease selected from a group comprising rheumatoid                arthritis, SLE, psoriatic arthritis, ankylosing                spondylitis, juvenile idiopathic arthritis or                osteoarthritis, or            -   a-2) Patients previously not treated for pain associated                with a group of inflammatory diseases comprising                rheumatoid arthritis, SLE, psoriatic arthritis,                ankylosing spondylitis, juvenile idiopathic arthritis,                or osteoarthritis, or            -   a-3) Patients treated for an inflammatory condition.        -   9a) A neutralizing antibody or a functional fragment thereof            specifically binding primate GM-CSF for use in the treatment            of pain emanating from an inflammatory disease selected from            a group comprising rheumatoid arthritis, SLE, psoriatic            arthritis, ankylosing spondylitis, juvenile idiopathic            arthritis and osteoarthritis,        -   wherein said disease is wherein the neutralizing antibody or            a functional fragment thereof specifically binding primate            GM-CSF is used according to the following dosing scheme:            -   (i) a first initial dose,            -   (ii) followed by administration of a second dose after                about 14 days after the first initial dose,            -   (iii) at least one further dose administered after 28                days after said second dose,            -   (iv) optionally followed by further doses administered                within intervals of about 28 days, and,        -   wherein the patients are selected from the following patient            subgroups:            -   a-1) Patients previously not treated for an inflammatory                disease selected from a group comprising rheumatoid                arthritis, SLE, psoriatic arthritis, ankylosing                spondylitis, juvenile idiopathic arthritis, and                osteoarthritis, or            -   a-2) Patients previously not treated for pain associated                with a group of inflammatory diseases comprising                rheumatoid arthritis, SLE, psoriatic arthritis,                ankylosing spondylitis, juvenile idiopathic arthritis,                and osteoarthritis, or            -   a-3) Patients treated for an inflammatory condition.        -   9b) A neutralizing antibody or a functional fragment thereof            specifically binding primate GM-CSF for use in the treatment            of pain emanating from an inflammatory disease selected from            a group comprising rheumatoid arthritis, psoriatic            arthritis, ankylosing spondylitis, juvenile idiopathic            arthritis, and osteoarthritis,        -   wherein said disease is wherein the neutralizing antibody or            a functional fragment thereof specifically binding primate            GM-CSF is used according to the following dosing scheme:            -   (i) a first initial dose,            -   (ii) followed by administration of a second dose after                about 14 days after the first initial dose,            -   (iii) at least one further dose administered after 28                days after said second dose,            -   (iv) optionally followed by further doses administered                within intervals of about 28 days, and,        -   wherein the patients are selected from the following patient            subgroups:            -   a-1) Patients previously not treated for an inflammatory                disease selected from a group comprising rheumatoid                arthritis, SLE, psoriatic arthritis, ankylosing                spondylitis, juvenile idiopathic arthritis and                osteoarthritis, or            -   a-2) Patients previously not treated for pain associated                with a group of inflammatory diseases comprising                rheumatoid arthritis, SLE, psoriatic arthritis,                ankylosing spondylitis, juvenile idiopathic arthritis,                or osteoarthritis, or            -   a-3) Patients treated for an inflammatory condition.        -   9c) A neutralizing antibody or a functional fragment thereof            specifically binding primate GM-CSF for use in the treatment            of pain emanating from rheumatoid arthritis,        -   wherein said disease is wherein the neutralizing antibody or            a functional fragment thereof specifically binding primate            GM-CSF is used according to the following dosing scheme:            -   (i) a first initial dose,            -   (ii) followed by administration of a second dose after                about 14 days after the first initial dose,            -   (iii) at least one further dose administered after 28                days after said second dose,            -   (iv) optionally followed by further doses administered                within intervals of about 28 days, and,        -   wherein the patients are selected from the following patient            subgroups:            -   a-1) Patients previously not treated for rheumatoid                arthritis, or            -   a-2) Patients previously not treated for pain associated                with rheumatoid arthritis, or            -   a-3) Patients treated for rheumatoid arthritis.        -   9d) The neutralizing antibody or a functional fragment            thereof specifically binding primate GM-CSF for use in the            treatment of pain emanating from rheumatoid arthritis,        -   wherein the neutralizing antibody or a functional fragment            thereof specifically binding primate GM-CSF is used            according to the following dosing scheme:            -   (i) a first initial dose,            -   (ii) followed by administration of a second dose after                about 14 days after the first initial dose,            -   (iii) at least one further dose administered after 28                days after said second dose,            -   (iv) optionally followed by further doses administered                within intervals of about 28 days, and,        -   wherein the patients are selected from the following patient            subgroups:            -   a-1) Patients previously not treated for rheumatoid                arthritis, or            -   a-2) Patients previously not treated for inflammatory                pain associated with rheumatoid arthritis, or            -   a-3) Patients treated for rheumatoid arthritis,        -   wherein the patients receive at least one additional            anti-inflammatory drug selected from the group comprising            DMARDs, corticosteroids, NSAIDS, opioids, and biologic            drugs.        -   9e) The neutralizing antibody or a functional fragment            thereof specifically binding primate GM-CSF for use in the            treatment of pain emanating from an inflammatory disease            according to item 9d), wherein the at least one additional            anti-inflammatory drug is methotrexate, which administered            at a dose of, e.g. 7.5 to 25 mg/weekly, such as at a dose of            7.5 to 15 mg/weekly or 15 to 25 mg/weekly.        -   9f) The neutralizing antibody or a functional fragment            thereof specifically binding primate GM-CSF for use in the            treatment of pain emanating from an inflammatory disease            according to item 9e), wherein the at least one additional            anti-inflammatory drug is methotrexate, which is            administered at a dose of 7.5 to 25 mg/weekly, such as at a            dose of 7.5 to 15 mg/weekly or 15 to 25 mg/weekly, and            wherein the neutralizing antibody or a functional fragment            thereof specifically binding primate GM-CSF is formulated            for subcutaneous administration.        -   9g) The neutralizing antibody or a functional fragment            thereof specifically binding primate GM-CSF for use in the            treatment of pain emanating from an inflammatory disease            -   (i) according to items 9a) to 9c), wherein the                neutralizing antibody or a functional fragment thereof                specifically binding primate GM-CSF is formulated for                subcutaneous administration, or            -   (ii) according to any one of items 9d)-9f), wherein the                at least one additional anti-inflammatory drug is                methotrexate, which is administered at a dose of 7.5 to                25 mg/weekly, e.g., at a dose of 7.5 to 15 mg/weekly or                15 to 25 mg/weekly, and wherein the neutralizing                antibody or a functional fragment thereof specifically                binding primate GM-CSF is formulated for subcutaneous                administration,            -   and wherein in any of (i) or (ii) the first initial dose                of said neutralizing antibody or functional fragment                thereof, as well as the second dose and optionally                further doses comprises a quantity of 10 to 50 mg.        -   9h) The neutralizing antibody or a functional fragment            thereof specifically binding primate GM-CSF for use in the            treatment of an inflammatory disease            -   (i) according to items 9a) to 9c), wherein the                neutralizing antibody or a functional fragment thereof                specifically binding primate GM-CSF is formulated for                subcutaneous administration,            -   (ii) or according to any one of items 9d) to 9g),                wherein the at least one additional anti-inflammatory                drug is methotrexate, which is administered at a dose of                7.5 to 25 mg/weekly, e.g., at a dose of 7.5 to 15                mg/weekly or 15 to 25 mg/weekly, and wherein the                neutralizing antibody or a functional fragment thereof                specifically binding primate GM-CSF is formulated for                subcutaneous administration,            -   and wherein in any of (i) or (ii) the first initial dose                of said neutralizing antibody or functional fragment                thereof, as well as the second dose and optionally                further doses comprises a quantity of 20 mg.        -   9i) The neutralizing antibody or a functional fragment            thereof specifically binding primate GM-CSF for use in the            treatment of an inflammatory disease            -   (i) according to items 9a) to 9c), wherein the                neutralizing antibody or a functional fragment thereof                specifically binding primate GM-CSF is formulated for                subcutaneous administration, or            -   (ii) according to any one of items 9d) to 9f), wherein                the at least one additional anti-inflammatory drug is                methotrexate, which is administered at a dose of 7.5 to                25 mg/weekly, e.g., at a dose of 7.5 to 15 mg/weekly or                15 to 25 mg/weekly, and wherein the neutralizing                antibody or a functional fragment thereof specifically                binding primate GM-CSF is formulated for subcutaneous                administration,            -   and wherein in any of (i) or (ii) the first initial dose                of said neutralizing antibody or functional fragment                thereof, as well as the second dose and optionally                further doses comprises a quantity of 25 to 100 mg.        -   9j) The neutralizing antibody or a functional fragment            thereof specifically binding primate GM-CSF for use in the            treatment of an inflammatory disease            -   (i) according to items 9a) to 9c), wherein the                neutralizing antibody or a functional fragment thereof                specifically binding primate GM-CSF is formulated for                subcutaneous administration, or            -   (ii) according to any one of items 9d) to 9f), wherein                the at least one additional anti-inflammatory drug is                methotrexate, which is administered at a dose of 7.5 to                25 mg/weekly, e.g., at a dose of 7.5 to 15 mg/weekly or                15 to 25 mg/weekly, and wherein the neutralizing                antibody or a functional fragment thereof specifically                binding primate GM-CSF is formulated for subcutaneous                administration,            -   and wherein in any of (i) or (ii) the first initial dose                of said neutralizing antibody or functional fragment                thereof, as well as the second dose and optionally                further doses comprises a quantity of 80 mg.        -   9k) The neutralizing antibody or a functional fragment            thereof specifically binding primate GM-CSF for use in the            treatment of an inflammatory disease            -   (i) according to items 9a) to 9c), wherein the                neutralizing antibody or a functional fragment thereof                specifically binding primate GM-CSF is formulated for                subcutaneous administration, or            -   (ii) according to any one of items 9d) to 9f), wherein                the at least one additional anti-inflammatory drug is                methotrexate, which is administered at a dose of 7.5 to                25 mg/weekly, e.g., at a dose of 7.5 to 15 mg/weekly or                15 to 25 mg/weekly, and wherein the neutralizing                antibody or a functional fragment thereof specifically                binding primate GM-CSF is formulated for subcutaneous                administration,            -   and wherein in any of (i) or (ii) the first initial dose                of said neutralizing antibody or functional fragment                thereof, as well as the second dose and optionally                further doses comprises a quantity of 50 to 300 mg.        -   9l) The neutralizing antibody or a functional fragment            thereof specifically binding primate GM-CSF for use in the            treatment of an inflammatory disease            -   (i) according to items 9a) to 9c), wherein the                neutralizing antibody or a functional fragment thereof                specifically binding primate GM-CSF is formulated for                subcutaneous administration, or            -   (ii) according to any one of items 9d) to 9f), wherein                the at least one additional anti-inflammatory drug is                methotrexate, which is administered at a dose of 7.5 to                25 mg/weekly, e.g., at a dose of 7.5 to 15 mg/weekly or                15 to 25 mg/weekly, and wherein the neutralizing                antibody or a functional fragment thereof specifically                binding primate GM-CSF is formulated for subcutaneous                administration,            -   and wherein in any of (i) or (ii) the first initial dose                of said neutralizing antibody or functional fragment                thereof, as well as the second dose and optionally                further doses comprises a quantity of 150 mg.        -   9m) The neutralizing antibody or a functional fragment            thereof specifically binding primate GM-CSF for use in the            treatment of pain emanating from an inflammatory disease            -   (i) according to items 9a) to 9c), wherein the                neutralizing antibody or a functional fragment thereof                specifically binding primate GM-CSF is formulated for                subcutaneous administration, or            -   (ii) according to any one of items 9d) to 9f), wherein                the at least one additional anti-inflammatory drug is                methotrexate, which is administered at a dose of 7.5 to                25 mg/weekly, e.g., at a dose of 7.5 to 15 mg/weekly or                15 to 25 mg/weekly, and wherein the neutralizing                antibody or a functional fragment thereof specifically                binding primate GM-CSF is formulated for subcutaneous                administration,            -   and wherein in any of (i) or (ii) the first initial dose                of said neutralizing antibody or functional fragment                thereof, as well as the second dose and optionally                further doses comprises a quantity of 20 mg, or of 80                mg, or of 150 mg,            -   and wherein in any of (i) or (ii) the pain is moderate,                moderate to severe or severe pain.        -   9n) The neutralizing antibody or a functional fragment            thereof specifically binding primate GM-CSF for use in the            treatment of pain emanating from an inflammatory disease            -   (i) according to items 9a) to 9c), wherein the                neutralizing antibody or a functional fragment thereof                specifically binding primate GM-CSF is formulated for                subcutaneous administration, or            -   (ii) according to any one of items 9d) to 9f), wherein                the at least one additional anti-inflammatory drug is                methotrexate, which is administered at a dose of 7.5 to                25 mg/weekly, e.g., at a dose of 7.5 to 15 mg/weekly or                15 to 25 mg/weekly,            -   and wherein the neutralizing antibody or a functional                fragment thereof specifically binding primate GM-CSF is                formulated for subcutaneous administration,            -   and wherein in any of (i) or (ii) the first initial dose                of said neutralizing antibody or functional fragment                thereof as well as the second dose and optionally                further doses comprises a quantity of 20 mg, or of 80                mg, or of 150 mg,            -   and wherein in any of (i) or (ii) the pain is moderate,                moderate to severe or severe pain,            -   and wherein in any of (i) or (ii) the neutralizing                antibody or a functional fragment thereof specifically                binding primate GM-CSF comprising a light chain variable                region set forth in SEQ ID No: 19 and a heavy chain                variable region set forth in SEQ ID NO: 21, or sequences                that are at least 70%, at least 75%, at least 80%, at                least 85%, at least 90%, at least 95%, at least 97%, or                at least 99%, identical with SEQ ID NO: 19 and/or with                SEQ ID NO: 21, e.g., a light chain amino acid sequence                as set out in SEQ ID NO: 34 and a heavy chain amino acid                sequence as set out in any of SEQ ID NOs: 35-48, e.g.,                SEQ ID NO: 35, or sequences that are at least 70%, at                least 75%, at least 80%, at least 85%, at least 90%, at                least 95%, at least 97%, or at least 99%, identical with                SEQ ID NO: 34 and/or with SEQ ID NOs: 35-48, e.g., with                SEQ ID NO:35.        -   9o) The neutralizing antibody or a functional fragment            thereof specifically binding primate GM-CSF for use in the            treatment of pain emanating from an inflammatory disease            -   (i) according to items 9a) to 9c), wherein the                neutralizing antibody or a functional fragment thereof                specifically binding primate GM-CSF is formulated for                subcutaneous administration, or            -   (ii) according to any one of items 9d) to 9f), wherein                the at least one additional anti-inflammatory drug is                methotrexate, which is administered at a dose of 7.5 to                25 mg/weekly, e.g., at a dose of 7.5 to 15 mg/weekly or                15 to 25 mg/weekly, wherein the neutralizing antibody or                a functional fragment thereof specifically binding                primate GM-CSF is formulated for subcutaneous                administration,            -   and wherein in any of (i) or (ii) the first initial dose                of said neutralizing antibody or functional fragment                thereof as well as the second dose and optionally                further doses comprises a quantity of 20 mg, or of 80                mg, or of 150 mg,            -   and wherein in any of (i) or (ii) the pain is moderate,                moderate to severe or severe pain,            -   and wherein in any of (i) or (ii) the neutralizing                antibody or a functional fragment thereof specifically                binding primate GM-CSF comprising a light chain variable                region set forth in SEQ ID No: 19 and a heavy chain                variable region set forth in SEQ ID NO: 21, or sequences                that are at least 70%, at least 75%, at least 80%, at                least 85%, at least 90%, at least 95%, at least 97%, or                at least 99%, identical with SEQ ID NO: 19 and/or with                SEQ ID NO: 21, e.g., a light chain amino acid sequence                as set out in SEQ ID NO: 34 and a heavy chain amino acid                sequence as set out in any of SEQ ID NOs: 35-48, e.g.,                SEQ ID NO: 35, or sequences that are at least 70%, at                least 75%, at least 80%, at least 85%, at least 90%, at                least 95%, at least 97%, or at least 99%, identical with                SEQ ID NO: 34 and/or with SEQ ID NOs: 35-48, e.g., with                SEQ ID NO:35,            -   and wherein in any of (i) or (ii) the subject has                moderate, moderate to severe, or severe rheumatoid                arthritis that is insufficiently controlled by either                methotrexate alone, or by methotrexate in combination                with at least one other chemical DMARD(s) and/or at                least one TNF-inhibitor.        -   9p) The neutralizing antibody or a functional fragment            thereof specifically binding primate GM-CSF for use in the            treatment of pain emanating from an inflammatory disease            -   (i) according to item items 9a) to 9c), wherein the                neutralizing antibody or a functional fragment thereof                specifically binding primate GM-CSF is formulated for                subcutaneous administration, or            -   (ii) according to any one of items 9d) to 9f), wherein                the at least one additional anti-inflammatory drug is                methotrexate, which is administered at a dose of 7.5 to                25 mg/weekly, e.g., at a dose of 7.5 to 15 mg/weekly or                15 to 25 mg/weekly, wherein the neutralizing antibody or                a functional fragment thereof specifically binding                primate GM-CSF is administered subcutaneously,            -   and wherein in any of (i) or (ii) the first initial dose                of said neutralizing antibody or functional fragment                thereof as well as the second dose and optionally                further doses comprises a quantity of 20 mg, or of 80                mg, or of 150 mg,            -   and wherein in any of (i) or (ii) the pain is moderate,                moderate to severe or severe pain,            -   and wherein in any of (i) or (ii) the neutralizing                antibody or a functional fragment thereof specifically                binding primate GM-CSF comprising a light chain variable                region set forth in SEQ ID No: 19 and a heavy chain                variable region set forth in SEQ ID NO: 21, or sequences                that are at least 70%, at least 75%, at least 80%, at                least 85%, at least 90%, at least 95%, at least 97%, or                at least 99%, identical with SEQ ID NO: 19 and/or with                SEQ ID NO: 21, a light chain amino acid sequence as set                out in SEQ ID NO: 34 and a heavy chain amino acid                sequence as set out in any of SEQ ID NOs: 35-48, e.g.,                SEQ ID NO: 35, or sequences that are at least 70%, at                least 75%, at least 80%, at least 85%, at least 90%, at                least 95%, at least 97%, or at least 99%, identical with                SEQ ID NO: 34 and/or with SEQ ID NOs: 35-48, with SEQ ID                NO:35,            -   and wherein in any of (i) or (ii) the subject has                moderate, moderate to severe, or severe rheumatoid                arthritis that is insufficiently controlled by either                methotrexate alone, or by methotrexate in combination                with one TNF-inhibitor.        -   9q) The neutralizing antibody or a functional fragment            thereof specifically binding primate GM-CSF for use in the            treatment of pain emanating from an inflammatory disease            -   (i) according to items 9a) to 9c), wherein the                neutralizing antibody or a functional fragment thereof                specifically binding primate GM-CSF is formulated for                subcutaneous administration, or            -   (ii) according to any one of items 9d) to 9f), wherein                the at least one additional anti-inflammatory drug is                methotrexate, which is administered at a dose of 7.5 to                25 mg/weekly, e.g., at a dose of 7.5 to 15 mg/weekly or                15 to 25 mg/weekly, wherein the neutralizing antibody or                a functional fragment thereof specifically binding                primate GM-CSF is administered subcutaneously,            -   and wherein in any of (i) or (ii) the first initial dose                of said neutralizing antibody or functional fragment                thereof as well as the second dose and optionally                further doses comprises a quantity of 20 mg, or of 80                mg, or of 150 mg,            -   and wherein in any of (i) or (ii) the pain is moderate,                moderate to severe or severe pain,            -   and wherein in any of (i) or (ii) the neutralizing                antibody or a functional fragment thereof specifically                binding primate GM-CSF comprising a light chain variable                region set forth in SEQ ID No: 19 and a heavy chain                variable region set forth in SEQ ID NO: 21, or sequences                that are at least 70%, at least 75%, at least 80%, at                least 85%, at least 90%, at least 95%, at least 97%, or                at least 99%, identical with SEQ ID NO: 19 and/or with                SEQ ID NO: 21, e.g., a light chain amino acid sequence                as set out in SEQ ID NO: 34 and a heavy chain amino acid                sequence as set out in any of SEQ ID NOs: 35-48, e.g.,                SEQ ID NO: 35, or sequences that are at least 70%, at                least 75%, at least 80%, at least 85%, at least 90%, at                least 95%, at least 97%, or at least 99%, identical with                SEQ ID NO: 34 and/or with SEQ ID NOs: 35-48, e.g., with                SEQ ID NO:35,            -   and wherein in any of (i) or (ii) the subject has                moderate, moderate to severe, or severe rheumatoid                arthritis that is insufficiently controlled by either                methotrexate alone, or by methotrexate in combination                with one TNF-inhibitor.        -   9r) The neutralizing antibody or a functional fragment            thereof specifically binding primate GM-CSF for use in the            treatment of pain emanating from an inflammatory disease            -   (i) according to items 9a) to 9c), wherein the                neutralizing antibody or a functional fragment thereof                specifically binding primate GM-CSF is formulated for                subcutaneous administration, or            -   (ii) according to any one of items 9d) to 9f), wherein                the at least one additional anti-inflammatory drug is                methotrexate, which is administered at a dose of 7.5 to                25 mg/weekly, e.g., at a dose of 7.5 to 15 mg/weekly or                15 to 25 mg/weekly,            -   and wherein the neutralizing antibody or a functional                fragment thereof specifically binding primate GM-CSF is                administered subcutaneously,            -   and wherein in any of (i) or (ii) the first initial dose                of said neutralizing antibody or functional fragment                thereof as well as the second dose and optionally                further doses comprises a quantity of 20 mg, or of 80                mg, or of 150 mg,            -   and wherein in any of (i) or (ii) the pain is moderate,                moderate to severe or severe pain,            -   and wherein the neutralizing antibody or a functional                fragment thereof specifically binding primate GM-CSF                comprising a light chain variable region set forth in                SEQ ID No: 19 and a heavy chain variable region set                forth in SEQ ID NO: 21, or sequences that are at least                70%, at least 75%, at least 80%, at least 85%, at least                90%, at least 95%, at least 97%, or at least 99%,                identical with SEQ ID NO: 19 and/or with SEQ ID NO: 21,                e.g., a light chain amino acid sequence as set out in                SEQ ID NO: 34 and a heavy chain amino acid sequence as                set out in any of SEQ ID NOs: 35-48, e.g., SEQ ID NO:                35, or sequences that are at least 70%, at least 75%, at                least 80%, at least 85%, at least 90%, at least 95%, at                least 97%, or at least 99%, identical with SEQ ID NO: 34                and/or with SEQ ID NOs: 35-48, e.g., with SEQ ID NO:35,            -   and wherein in any of (i) or (ii) the subject has                moderate, moderate to severe, or severe rheumatoid                arthritis that is insufficiently controlled by either                methotrexate alone, or by methotrexate in combination                with one TNF-inhibitor,            -   and wherein in any of (i) or (ii) the administration of                the neutralizing antibody or functional fragment alone                or in a combination therapy with methotrexate or another                anti-folate compound thereof induces ACR20/50/70 scores                of ≥50%/20%/10% at 24 weeks in TNF non-responders, or                ≥55%/30%/10% in methotrexate non-responders.        -   9s) The neutralizing antibody or a functional fragment            thereof specifically binding primate GM-CSF for use in the            treatment of pain emanating from an inflammatory disease            -   (i) according to items 9a) to 9c), wherein the                neutralizing antibody or a functional fragment thereof                specifically binding primate GM-CSF is formulated for                subcutaneous administration, or            -   (ii) according to any one of items 9d) to 9f), wherein                the at least one additional anti-inflammatory drug is                methotrexate, which is administered at a dose of 7.5 to                25 mg/weekly, e.g., at a dose of 7.5 to 15 mg/weekly or                15 to 25 mg/weekly, and wherein the neutralizing                antibody or a functional fragment thereof specifically                binding primate GM-CSF is administered subcutaneously,            -   and wherein in any of (i) or (ii) the first initial dose                of said neutralizing antibody or functional fragment                thereof as well as the second dose and optionally                further doses comprises a quantity of 20 mg, or of 80                mg, or of 150 mg,            -   and wherein in any of (i) or (ii) the pain is moderate,                moderate to severe or severe pain,            -   and wherein in any of (i) or (ii) the neutralizing                antibody or a functional fragment thereof specifically                binding primate GM-CSF comprising a light chain variable                region set forth in SEQ ID No: 19 and a heavy chain                variable region set forth in SEQ ID NO: 21, or sequences                that are at least 70%, at least 75%, at least 80%, at                least 85%, at least 90%, at least 95%, at least 97%, or                at least 99%, identical with SEQ ID NO: 19 and/or with                SEQ ID NO: 21, e.g., a light chain amino acid sequence                as set out in SEQ ID NO: 34 and a heavy chain amino acid                sequence as set out in any of SEQ ID NOs: 35-48, e.g.,                SEQ ID NO: 35, or sequences that are at least 70%, at                least 75%, at least 80%, at least 85%, at least 90%, at                least 95%, at least 97%, or at least 99%, identical with                SEQ ID NO: 34 and/or with SEQ ID NOs: 35-48, e.g., with                SEQ ID NO:35,            -   and wherein in any of (i) or (ii) the subject has                moderate, moderate to severe, or severe rheumatoid                arthritis that is insufficiently controlled by either                methotrexate alone, or by methotrexate in combination                with one TNF-inhibitor, and wherein in any of (i)                or (ii) the disease activity (DAS28CRP) at least 12                weeks subsequent to the start of treatment, e.g., at                least 24 weeks subsequent to the start of treatment is                reduced to a score of <3.2, e.g., <2.6.    -   10. The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        pain emanating from an inflammatory disease according to item 9        including any of items 9a) to 9s),        -   wherein the neutralizing antibody or a functional fragment            thereof specifically binding primate GM-CSF is used            according to the following dosing scheme:            -   (i) a first initial dose,            -   (ii) followed by administration of a second dose after                about 14 days,            -   (iii) at least one further dose administered after 28                days after said second dose,            -   (iv) optionally followed by further doses administered                within intervals of about 28 days, and        -   wherein the patients are selected from the following            subgroups:    -   a-1) Patients not treated for an inflammatory condition or for        pain, further selected from        -   individuals with RA that have not previously been treated            for RA, or        -   individuals that have not previously been treated for RA who            were diagnosed as RA patients at least 6 months prior to the            first initial dose, at least 1 year prior to the first            initial dose, 2 years prior to the first initial dose, 3            years prior to the first initial dose, 4 years prior to the            first initial dose, or more than 5 years prior to the first            initial dose, or    -   a-2) Patients treated for RA who have not received medication        for pain in addition to the treatment for RA,    -   a-3) Patients treated for an inflammatory condition, selected        from the group comprising rheumatoid arthritis, SLE, psoriatic        arthritis, ankylosing spondylitis, juvenile idiopathic        arthritis, and osteoarthritis selected from the following        subgroups:        -   patients receiving a non-biologic DMARD treatment, but who            have previously not been treated with biologics (biologics            treatment naïve),        -   patients receiving a treatment with anti-folate compounds,            e.g., methotrexate, or other DMARS and/or glucocorticoids,        -   patients receiving a treatment with anti-folate compounds,            e.g., a stable dose of methotrexate at about >15 mg/week for            at least 12 weeks and who do not suffer from neutropenia,        -   patients that are treated with methotrexate for at least 3            months, wherein said patients further receiving folinic acid            or folic acid on the days after methotrexate administration,            but not on the day when methotrexate is administered,        -   patients that are treated with methotrexate but not            co-treated with adenosine receptor antagonists selected from            a group comprising theophylline and caffeine,        -   patients that are treated with methotrexate without any            signs of marrow suppression, said signs comprising            neutropenia, for at least 12 weeks after initial            administration of weekly doses of 7.5-25 mg per week, e.g.,            after initial administration of weekly doses of 7.5-15 mg            per week,        -   Patients that are treated with methotrexate, which having a            genetic polymorphism in at least one thymidylate synthase            gene, the AICAR transformylase gene, or the RFC1 gene;        -   patients without polymorphism at C677T in the MTHFR            (methylene tetrahydrofolate reductase gene),        -   patients with insufficiently controlled RA treated with            methotrexate for at least 3 months with moderate, moderate            to severe, or severe disease activity,        -   patients with insufficiently controlled RA treated with            DMARDs, e.g. those selected from sulfasalazine, leflunomide            or hydroxychloroquine, for at least 3 months with moderate,            moderate to severe, or severe disease activity,        -   patients with moderate, moderate to severe, or severe            disease activity insufficiently controlled RA treated with            methotrexate for at least 3 months in combination with            another non-biologic (chemical) DMARD, e.g., an anti-folate            compound, e.g., methotrexate,        -   patients with moderate, moderate to severe, or severe            disease activity insufficiently controlled RA treated with            methotrexate for at least 3 months in combination with            another biologic DMARD, e.g., antagonists of IL-6R, IL-6, or            IL-17;        -   patients selected from the group of individuals receiving            non-biologic DMARD treatment, e.g., treatment with an            anti-folate compound, e.g., treatment with methotrexate,            plus biologic treatment, wherein the biologic treatment is            selected from the group of compounds comprising            -   anti-cytokine antagonists selected from a group chemical                antagonists and antibodies or derivatives thereof,            -   cytokine receptor antagonists selected from a group                comprising chemical antagonists and antibodies or                derivatives thereof,            -   TNF-alpha neutralising agents selected from a group                comprising chemical neutralising agents and antibodies                or derivatives thereof,            -   IL-1 neutralising agents selected from a group                comprising chemical neutralising agents and antibodies                or derivatives thereof,            -   IL-6 neutralising agents selected from a group                comprising chemical neutralising agents and antibodies                or derivatives thereof,        -   IL-6R neutralising agents selected from a group comprising            chemical neutralising agents and antibodies or derivatives            thereof,            -   CD20 neutralising agents selected from a group                comprising chemical neutralising agents and antibodies                or derivatives thereof,        -   IL-17 antagonists selected from a group comprising chemical            neutralising agents and antibodies or derivatives thereof,            and        -   patients with insufficiently controlled RA treated with            methotrexate for at least 3 months in combination with a            biologic DMARD with moderate, moderate to severe, or severe            disease activity,    -   a-4) Patients treated for pain comprising individuals selected        from the follow subgroups of patients:        -   patients treated for pain associated with a disease other            than rheumatoid arthritis, wherein said disease is selected            from autoimmune diseases, neuropathies, or inflammatory            diseases,        -   patients treated with methotrexate for at least 3 months in            combination with a biologic DMARD with moderate/moderate to            severe/severe disease activity, wherein the pain is            insufficiently controlled by the treatment        -   patients with a non-biologic DMARD treatment and reduction            of RA signs and symptoms and inhibition of progression of            structural damage, wherein the pain persists or remits,        -   patients with no signs of ongoing inflammation, where pain            in the joints is still present,        -   patients insufficiently controlled on methotrexate,        -   patients who were insufficiently controlled on methotrexate            plus TNF inhibitor treatment;        -   patients who were insufficiently controlled on treatment            with sulfasalazine, hydroxychloroquine, and/or leflunomide,        -   patients that do not suffer from neutropenia (or optionally            those that do not suffer from a cancer); or        -   patients that have not been treated with GM-CSF prior to the            first initial dose;        -   patients that have previously not been treated to correct            chemotherapy induced cytopenias and to counteract            cytopenia-related predisposition to infections and            hemorrhages,        -   patients that do not suffer from respiratory tract problems,            particularly lung problems associated with infections.    -   11. A neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        pain emanating from an inflammatory disease as defined in any        one of items 1 to 10, wherein the administration of the second        dose is omitted, thereby having the doses after the first        initial dose administered in intervals of 21-35 days,        specifically 28 days.    -   12. The neutralizing antibody or functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        pain emanating from an inflammatory disease as defined in any        one of items 1 to 11, wherein the pain is mild, mild to        moderate, e.g., moderate, moderate to severe or severe pain.    -   13. The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        pain emanating from an inflammatory disease as defined in any        one of items 1 to 12, wherein the antibody is formulated for        subcutaneous administration.    -   14. The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        pain emanating from an inflammatory disease as defined in any        one of items 1 to 13, the first initial dose of said        neutralizing antibody or functional fragment thereof, as well as        the second dose and optionally further doses comprises a        quantity of 10 to 50 mg, or a quantity of 25 to 100 mg, or a        quantity of 50 to 300 mg.    -   15. The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        pain emanating from an inflammatory disease as defined in any        one of items 1 to 14, wherein the first initial dose of said        neutralizing antibody or functional fragment thereof, as well as        the second dose and optionally further doses comprises a        quantity of 20 mg, or of 80 mg, or of 150 mg.    -   16. The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        pain emanating from an inflammatory disease as defined in any        one of items 1 to 15, wherein said antibody comprises a light        chain variable region comprising an amino acid sequence as set        out in SEQ ID NOs: 19, 34, 54 or 55, and a heavy chain variable        region comprising an amino acid sequence chosen from the group        consisting of those set out in any of the SEQ ID NOs: 20-33,        35-48, 52 or 53, e.g., said antibody comprises a light chain        variable region comprising an amino acid sequence as set out in        SEQ ID NO: 19, and a heavy chain variable region comprising an        amino acid sequence set out in SEQ ID NO: 21.    -   17. The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        pain emanating from an inflammatory disease as defined in any        one of items 1 to 16, wherein said neutralizing antibody or        functional fragment thereof comprises in its heavy chain        variable region a CDR3 comprising an amino acid sequence chosen        from the group consisting of those set out in any of the SEQ ID        NOs: 1-13 or 56.    -   18. The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        pain emanating from an inflammatory disease as defined in any        one of items 1 to 17, wherein said neutralizing antibody or        functional fragment thereof comprises a heavy chain variable        region CDR3 sequence set out in any of the amino acid sequences        in SEQ ID NOs: 1-13 or 56 together with the heavy chain variable        region CDR1 sequence set out in the amino acid sequence of SEQ        ID NO: 14 and heavy chain variable region CDR2 sequence set out        in the amino acid sequence of SEQ ID NO: 15.    -   19. The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        pain emanating from an inflammatory disease as defined in any        one of items 1 to 18, wherein said neutralizing antibody or        functional fragment thereof comprises in its light chain        variable region a CDR1 comprising the amino acid sequence set        out in SEQ ID NO: 16, a CDR2 comprising the amino acid sequence        set out in SEQ ID NO: 17, and a CDR3 comprising the amino acid        sequence set out in SEQ ID NO: 18.    -   20. The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        pain emanating from an inflammatory disease as defined in any        one of items 1 to 19, wherein said neutralizing antibody or        functional fragment thereof comprises in its light chain        variable region a CDR1 comprising an amino acid sequence as set        out in SEQ ID NO: 16, a CDR2 having an amino acid sequence as        set out in SEQ ID NO: 17 and a CDR3 having an amino acid        sequence as set out in SEQ ID NO: 18; and comprising in its        heavy chain variable region a CDR1 region comprising an amino        acid sequence as set out in SEQ ID NO: 14, a CDR2 region having        an amino acid sequence as set out in SEQ ID NO: 15 and a CDR3        having an amino acid sequence as set out in any of SEQ ID Nos:        1-13 or 56, e.g., SEQ ID No. 2.    -   21. The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        pain emanating from an inflammatory disease as defined in any        one of items 1 to 20, comprising a light chain amino acid        sequence as set out in SEQ ID NO: 34 and a heavy chain amino        acid sequence as set out in any of SEQ ID NOs: 35-48, e.g., SEQ        ID NO: 35.    -   22. The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        pain emanating from an inflammatory disease as defined in any        one of items 1 to 21, wherein said neutralizing antibody or        functional fragment thereof comprises an amino acid sequence        bearing at least 70%, at least 80%, at least 85%, at least 90%,        at least 95% homology to the respective amino acid sequence as        set out in any of SEQ ID NOs: 1-48 and/or 52-56.    -   23. The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        pain emanating from an inflammatory disease as defined in any        one of items 1 to 22, wherein additionally at least one further        analgesic compound is used.    -   24. The neutralizing anti-primate GM-CSF antibody or functional        fragment thereof for use according to any one of items 1 to 23,        wherein the at least one further analgesic compound is selected        from the group comprising oral corticosteroids, e.g.,        prednisolone or codeine.    -   25. A method of treatment of pain in a patient comprising        administering the neutralizing antibody or a functional fragment        thereof specifically binding primate GM-CSF as defined in any        one of items 1 to 24.    -   26. The method according to any one of item 25, wherein the pain        is associated with mild, mild to moderate, moderate, moderate to        severe or severe rheumatoid arthritis, e.g., moderate, moderate        to severe or severe rheumatoid arthritis.    -   27. The method according to any one of items 25 or 26, wherein        the subject has moderate, moderate to severe, or severe        rheumatoid arthritis that is insufficiently controlled by either        methotrexate alone, or by methotrexate in combination with at        least one other chemical DMARD(s) and/or at least one        TNF-inhibitor and/or at least one inhibitor of a cytokine        different from TNF, e.g. an IL-6R inhibitor.    -   28. The method according to any one of items 25 to 27, wherein        neutralizing antibody or functional fragment thereof is        administered parenterally, e.g., subcutaneously.    -   29. The method according to any one of items 25 to 28, wherein        the neutralizing antibody or functional fragment thereof as        defined in any of the preceding claims is administered        subcutaneously in at least 3, at least 5, at least 7 doses over        a period of at least 21 weeks.    -   30. The method according to any one of items 25 to 29, wherein        the administration of the neutralizing antibody or functional        fragment alone or in a combination therapy with methotrexate or        another anti-folate compound thereof induces ACR20/50/70 scores        of ≥50%/20%/10% at 24 weeks in TNF non-responders, or        ≥55%/30%/10% in methotrexate non-responders.    -   31. The method according to any one of items 25 to 30, wherein        the treatment alleviates fatigue and/or sleeping disturbances        associated with pain.    -   32. The method according to any one of items 25 to 31, wherein        the patient's pain symptoms remit for at least 1 year subsequent        to the start of treatment.    -   33. The method according to any one of items 25 to 32, wherein        structural joint damages does not advance for at least 1 year        subsequent to the start of treatment.    -   34. The method according to any one of items 25 to 33, wherein        the disease activity (DAS28CRP) at least 12 weeks subsequent to        the start of treatment, at least 24 weeks subsequent to the        start of treatment is reduced to a score of <3.2, e.g., <2.6.    -   35. The method according to any one of items 25 to 34, wherein        the serum levels contains at least 20%, at least 25%, at least        30%, at least 40%, at least 50% of the neutralizing anti-primate        GM-CSF antibody or functional fragment thereof seven days, for        at least 14 days, e.g., for at least 21 days, for at least 28        days after the last administration.

Preferred aspects relating to antibodies neutralizing GM-CSF relate to:

-   -   1. A neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        an inflammatory disease selected from a group comprising        rheumatoid arthritis, SLE, psoriatic arthritis, ankylosing        spondylitis, juvenile idiopathic arthritis, and osteoarthritis,        -   wherein the neutralizing antibody or a functional fragment            specifically binding primate GM-CSF is used according to the            following dosing scheme:            -   (i) a first initial dose,            -   (ii) followed by administration of a second dose within                a period of 7-21 days after the first initial dose,            -   (iii) at least one further dose administered within a                period of 21-35 days after said second dose,            -   (iv) optionally followed by further doses administered                within intervals of 21-35 days.    -   2. The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        an inflammatory disease according to item 1, wherein said        disease is selected from a group comprising rheumatoid        arthritis, SLE, psoriatic arthritis, ankylosing spondylitis,        juvenile idiopathic arthritis, and osteoarthritis,        -   wherein the neutralizing antibody or a functional fragment            specifically binding primate GM-CSF is used according to the            following dosing scheme:            -   (i) a first initial dose,            -   (ii) followed by administration of a second dose after                about 14 days after the first initial dose,            -   (iii) at least one further dose administered after about                28 days after said second dose,            -   (iv) optionally followed by further doses administered                within intervals of about 28 days.    -   3. The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        an inflammatory disease according to item 1 or 2, wherein said        disease is selected from a group comprising rheumatoid        arthritis, SLE, psoriatic arthritis, ankylosing spondylitis,        juvenile idiopathic arthritis, and osteoarthritis,        -   wherein the neutralizing antibody or a functional fragment            specifically binding primate GM-CSF is used according to the            following dosing scheme:            -   (i) a first initial dose,            -   (ii) followed by administration of a second dose after                about 14 days after the first initial dose,            -   (iii) at least one further dose administered after about                28 days after said second dose,            -   (iv) optionally followed by further doses administered                within intervals of about 28 days, and        -   wherein the patients receive at least one additional            anti-inflammatory drug selected from the group comprising            DMARDs, corticosteroids, e.g., glucocorticoids, NSAIDS,            opioids, and biologic drugs.    -   4. The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        an inflammatory disease according to items 1 to 3, wherein said        disease is selected from a group comprising rheumatoid        arthritis, SLE, psoriatic arthritis, ankylosing spondylitis,        juvenile idiopathic arthritis, and osteoarthritis,        -   wherein the neutralizing antibody or a functional fragment            specifically binding primate GM-CSF is used according to the            following dosing scheme:            -   (i) a first initial dose,            -   (ii) followed by administration of a second dose after                about 14 days after the first initial dose,            -   (iii) at least one further dose administered after about                28 days after said second dose,            -   (iv) optionally followed by further doses administered                within intervals of about 28 days, and        -   wherein the at least one additional anti-inflammatory drug            is selected from anti-folate compounds.    -   5. The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        an inflammatory disease according to items 1 to 4, wherein said        disease is selected from a group comprising rheumatoid        arthritis, SLE, psoriatic arthritis, ankylosing spondylitis,        juvenile idiopathic arthritis, and osteoarthritis,        -   wherein the neutralizing antibody or a functional fragment            thereof specifically binding primate GM-CSF is used            according to the following dosing scheme:            -   (i) a first initial dose,            -   (ii) followed by administration of a second dose after                about 14 days after the first initial dose,            -   (iii) at least one further dose administered after about                28 days after said second dose,            -   (iv) optionally followed by further doses administered                within intervals of about 28 days, and        -   wherein the anti-folate compound is methotrexate.    -   6. The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        an inflammatory disease according to items 1 to 5, wherein said        disease is selected from a group comprising rheumatoid        arthritis, SLE, psoriatic arthritis, ankylosing spondylitis,        juvenile idiopathic arthritis, and osteoarthritis,        -   wherein the neutralizing antibody or a functional fragment            thereof specifically binding primate GM-CSF is used            according to the following dosing scheme:            -   (i) a first initial dose,            -   (ii) followed by administration of a second dose after                about 14 days after the first initial dose,            -   (iii) at least one further dose administered after about                28 days after said second dose,            -   (iv) optionally followed by further doses administered                within intervals of about 28 days, and        -   wherein the methotrexate is administered once weekly.    -   7. The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        an inflammatory disease according to items 1 to 6, wherein said        disease is selected from a group comprising rheumatoid        arthritis, SLE, psoriatic arthritis, ankylosing spondylitis,        juvenile idiopathic arthritis, and osteoarthritis,        -   wherein the neutralizing antibody or a functional fragment            thereof specifically binding primate GM-CSF is used            according to the following dosing scheme:            -   (i) a first initial dose,            -   (ii) followed by administration of a second dose after                about 14 days after the first initial dose,            -   (iii) at least one further dose administered after about                28 days after said second dose,            -   (iv) optionally followed by further doses administered                within intervals of about 28 days, and        -   wherein the at least one additional anti-inflammatory drug            is methotrexate that is administered once a week at a dose            per administration of 7.5 to 25 mg, e.g., 15-25 mg, or 7.5            to 15 mg.    -   8. The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        an inflammatory disease according to items 1 to 7, wherein said        disease is selected from a group comprising rheumatoid        arthritis, SLE, psoriatic arthritis, ankylosing spondylitis,        juvenile idiopathic arthritis, and osteoarthritis,        -   wherein the neutralizing antibody or a functional fragment            thereof specifically binding primate GM-CSF is used            according to the following dosing scheme:            -   (ii) followed by administration of a second dose after                about 14 days after the first initial dose,            -   (iii) at least one further dose administered after about                28 days after said second dose,            -   (iv) optionally followed by further doses administered                within intervals of about 28 days, and        -   wherein the antibody is formulated for subcutaneous            administration.    -   9. A neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        an inflammatory disease selected from a group comprising        rheumatoid arthritis, SLE, psoriatic arthritis, ankylosing        spondylitis, juvenile idiopathic arthritis, and osteoarthritis,        -   wherein said disease is wherein the neutralizing antibody or            a functional fragment thereof specifically binding primate            GM-CSF is used according to the following dosing scheme:            -   (i) a first initial dose,            -   (ii) followed by administration of a second dose within                a period of 7-21 days after the first initial dose,            -   (iii) at least one further dose administered within a                period of 21-35 days after said second dose,            -   (iv) optionally followed by further doses administered                within intervals of 21-35 days,        -   wherein the patients are selected from the following patient            subgroups:            -   a-1) Patients not treated for an inflammatory disease                selected from a group comprising rheumatoid arthritis,                SLE, psoriatic arthritis, ankylosing spondylitis,                juvenile idiopathic arthritis, and osteoarthritis, or            -   a-2) Patients treated for an inflammatory condition.

9a) A neutralizing antibody or a functional fragment thereofspecifically binding primate GM-CSF for use in the treatment of aninflammatory disease selected from a group comprising rheumatoidarthritis, SLE, psoriatic arthritis, ankylosing spondylitis, juvenileidiopathic arthritis and osteoarthritis,

-   -   wherein said disease is wherein the neutralizing antibody or a        functional fragment thereof specifically binding primate GM-CSF        is used according to the following dosing scheme:        -   (v) a first initial dose,        -   (vi) followed by administration of a second dose after about            14 days after the first initial dose,        -   (vii) at least one further dose administered after 28 days            after said second dose,        -   (viii) optionally followed by further doses administered            within intervals of about 28 days, and,    -   wherein the patients are selected from the following patient        subgroups:        -   a-1) Patients previously not treated for an inflammatory            disease selected from a group comprising rheumatoid            arthritis, SLE, psoriatic arthritis, ankylosing spondylitis,            juvenile idiopathic arthritis, or osteoarthritis, or        -   a-2) Patients treated for an inflammatory condition.

9b) A neutralizing antibody or a functional fragment thereofspecifically binding primate GM-CSF for use in the treatment of aninflammatory disease selected from a group comprising rheumatoidarthritis, psoriatic arthritis, ankylosing spondylitis, juvenileidiopathic arthritis, or osteoarthritis,

-   -   wherein said disease is wherein the neutralizing antibody or a        functional fragment thereof specifically binding primate GM-CSF        is used according to the following dosing scheme:        -   (v) a first initial dose,        -   (vi) followed by administration of a second dose after about            14 days after the first initial dose,        -   (vii) at least one further dose administered after 28 days            after said second dose,        -   (viii) optionally followed by further doses administered            within intervals of about 28 days, and,    -   wherein the patients are selected from the following patient        subgroups:        -   a-1) Patients previously not treated for an inflammatory            disease selected from a group comprising rheumatoid            arthritis, SLE, psoriatic arthritis, ankylosing spondylitis,            juvenile idiopathic arthritis and osteoarthritis, or        -   a-2) Patients previously not treated for inflammatory pain            associated with a group of inflammatory diseases comprising            rheumatoid arthritis, SLE, psoriatic arthritis, ankylosing            spondylitis, juvenile idiopathic arthritis, and            osteoarthritis, or        -   a-3) Patients treated for an inflammatory condition.

9c) A neutralizing antibody or a functional fragment thereofspecifically binding primate GM-CSF for use in the treatment ofrheumatoid arthritis,

-   -   wherein said disease is wherein the neutralizing antibody or a        functional fragment thereof specifically binding primate GM-CSF        is used according to the following dosing scheme:        -   (v) a first initial dose,        -   (vi) followed by administration of a second dose after about            14 days after the first initial dose,        -   (vii) at least one further dose administered after 28 days            after said second dose,        -   (viii) optionally followed by further doses administered            within intervals of about 28 days, and,    -   wherein the patients are selected from the following patient        subgroups:        -   a-1) Patients previously not treated for rheumatoid            arthritis, or        -   a-2) Patients previously not treated for inflammatory pain            associated with rheumatoid arthritis, or        -   a-3) Patients treated for rheumatoid arthritis.

9d) The neutralizing antibody or a functional fragment thereofspecifically binding primate GM-CSF for use in the treatment ofrheumatoid arthritis,

-   -   wherein the neutralizing antibody or a functional fragment        specifically binding primate GM-CSF is used according to the        following dosing scheme:        -   (v) a first initial dose,        -   (vi) followed by administration of a second dose after about            14 days,        -   (vii) at least one further dose administered after 28 days            after said second dose,        -   (viii) optionally followed by further doses administered            within intervals of about 28 days, and,    -   wherein the patients are selected from the following patient        subgroups:        -   a-1) Patients previously not treated for rheumatoid            arthritis, or        -   a-2) Patients previously not treated for inflammatory pain            associated with rheumatoid arthritis, or        -   a-3) Patients treated for rheumatoid arthritis,    -   wherein the patients receive at least one additional        anti-inflammatory drug selected from the group comprising        DMARDs, corticosteroids, NSAIDS, opioids, and biologic drugs.    -   9e) The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        an inflammatory disease according to item 9d), wherein the at        least one additional anti-inflammatory drug is methotrexate,        which administered at a dose of, e.g. 15-25 mg, or 7.5 to 25        mg/weekly, such as at a dose of 7.5 to 15 mg/weekly.    -   9f) The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        an inflammatory disease according to item 9e), wherein the at        least one additional anti-inflammatory drug is methotrexate,        which is administered at a dose of 15-25 mg, or 7.5 to 25        mg/weekly, such as at a dose of 7.5 to 15 mg/weekly, and wherein        the neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF is formulated for        subcutaneous administration.    -   9g) The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        an inflammatory disease    -   (i) according to any one of items 9a) to 9c), wherein the        neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF is formulated for        subcutaneous administration, wherein the first initial dose of        said neutralizing antibody or functional fragment thereof, as        well as the second dose and optionally further doses comprises a        quantity of 10 to 50 mg, or    -   (ii) according to any one of items 9d)-9f), wherein the at least        one additional anti-inflammatory drug is methotrexate, which is        administered at a dose of 7.5 to 25 mg/weekly, e.g., at a dose        of 15-25 mg, or 7.5 to 15 mg/weekly, and wherein the        neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF is formulated for        subcutaneous administration, and wherein the first initial dose        of said neutralizing antibody or functional fragment thereof, as        well as the second dose and optionally further doses comprises a        quantity of 10 to 50 mg.    -   9h) The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        an inflammatory disease    -   (i) according to any one of items 9a) to 9c), wherein the        neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF is formulated for        subcutaneous administration, or    -   (ii) according to any one of items 9d)-9f), wherein the at least        one additional anti-inflammatory drug is methotrexate, which is        administered at a dose of 15-25 mg, or 7.5 to 25 mg/weekly,        e.g., at a dose of 7.5 to 15 mg/weekly, and wherein the        neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF is formulated for        subcutaneous administration,    -   and wherein in any of (i) or (ii) the first initial dose of said        neutralizing antibody or functional fragment thereof, as well as        the second dose and optionally further doses comprises a        quantity of 20 mg.    -   9i) The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        an inflammatory disease    -   (i) according to any one of items 9a) to 9c), wherein the        neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF is formulated for        subcutaneous administration, or    -   (ii) according to any one of items 9d)-9f), wherein the at least        one additional anti-inflammatory drug is methotrexate, which is        administered at a dose of 7.5 to 25 mg/weekly, e.g., at a dose        of 15-25 mg, or 7.5 to 15 mg/weekly, and wherein the        neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF is formulated for        subcutaneous administration,    -   and wherein in any of (i) or (ii) the first initial dose of said        neutralizing antibody or functional fragment thereof, as well as        the second dose and optionally further doses comprises a        quantity of 25 to 100 mg.    -   9j) The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        an inflammatory disease    -   (i) according to any one of items 9a) to 9c), wherein the        neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF is formulated for        subcutaneous administration, or    -   (ii) according to any one of items 9d)-9f), wherein the at least        one additional anti-inflammatory drug is methotrexate, which is        administered at a dose of 7.5 to 25 mg/weekly, e.g., at a dose        of 15-25 mg, or 7.5 to 15 mg/weekly, and wherein the        neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF is formulated for        subcutaneous administration,    -   and wherein in any of (i) or (ii) the first initial dose of said        neutralizing antibody or functional fragment thereof, as well as        the second dose and optionally further doses comprises a        quantity of 80 mg.    -   9k) The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        an inflammatory disease    -   (i) according to any one of items 9a) to 9c), wherein the        neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF is formulated for        subcutaneous administration, or    -   (ii) according to any one of items 9d)-9f), wherein the at least        one additional anti-inflammatory drug is methotrexate, which is        administered at a dose of 7.5 to 25 mg/weekly, e.g., at a dose        of 15-25 mg, or 7.5 to 15 mg/weekly, and wherein the        neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF is formulated for        subcutaneous administration,    -   and wherein in any of (i) or (ii) the first initial dose of said        neutralizing antibody or functional fragment thereof, as well as        the second dose and optionally further doses comprises a        quantity of 50 to 300 mg.    -   9l) The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        an inflammatory disease    -   (i) according to any one of items 9a) to 9c), wherein the        neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF is formulated for        subcutaneous administration, or    -   (ii) according to any one of items 9d)-9f), wherein the at least        one additional anti-inflammatory drug is methotrexate, which is        administered at a dose of 7.5 to 25 mg/weekly, e.g., at a dose        of 15-25 mg, or 7.5 to 15 mg/weekly, and wherein the        neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF is formulated for        subcutaneous administration,    -   and wherein in any of (i) or (ii) the first initial dose of said        neutralizing antibody or functional fragment thereof, as well as        the second dose and optionally further doses comprises a        quantity of 150 mg.    -   9m) The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        an inflammatory disease    -   (i) according to any one of items 9a) to 9c), wherein the        neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF is formulated for        subcutaneous administration, or    -   (ii) according to any one of items 9d)-9f), wherein the at least        one additional anti-inflammatory drug is methotrexate, which is        administered at a dose of 7.5 to 25 mg/weekly, e.g., at a dose        of 15-25 mg, or 7.5 to 15 mg/weekly, and wherein the        neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF is formulated for        subcutaneous administration,    -   and wherein in any of (i) or (ii) the first initial dose of said        neutralizing antibody or functional fragment thereof, as well as        the second dose and optionally further doses comprises a        quantity of 20 mg, or of 80 mg, or of 150 mg,    -   and wherein in any of (i) or (ii) the pain is moderate, moderate        to severe or severe pain.    -   9n) The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        an inflammatory disease    -   (i) according to 9a) to 9c), wherein the neutralizing antibody        or a functional fragment thereof specifically binding primate        GM-CSF is formulated for subcutaneous administration, or    -   (ii) according to any one of items 9d) to 9f), wherein the at        least one additional anti-inflammatory drug is methotrexate,        which is administered at a dose of 7.5 to 25 mg/weekly, e.g., at        a dose of 15-25 mg, or 7.5 to 15 mg/weekly, and wherein the        neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF is formulated for        subcutaneous administration,    -   and wherein in any of (i) or (ii) the first initial dose of said        neutralizing antibody or functional fragment thereof, as well as        the second dose and optionally further doses comprises a        quantity of 20 mg, or of 80 mg, or of 150 mg,    -   and wherein in any of (i) or (ii) the pain is moderate, moderate        to severe or severe pain,    -   and wherein in any of (i) or (ii) the neutralizing antibody or a        functional fragment thereof specifically binding primate GM-CSF        comprising a light chain variable region set forth in SEQ ID No:        19 and a heavy chain variable region set forth in SEQ ID NO: 21,        or sequences that are at least 70%, at least 75%, at least 80%,        at least 85%, at least 90%, at least 95%, at least 97%, or at        least 99%, identical with SEQ ID NO: 19 and/or with SEQ ID NO:        21, e.g., a light chain amino acid sequence as set out in SEQ ID        NO: 34 and a heavy chain amino acid sequence as set out in any        of SEQ ID NOs: 35-48, e.g., SEQ ID NO: 35, or sequences that are        at least 70%, at least 75%, at least 80%, at least 85%, at least        90%, at least 95%, at least 97%, or at least 99%, identical with        SEQ ID NO: 34 and/or with SEQ ID NOs: 35-48, e.g., with SEQ ID        NO:35.    -   9o) The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        an inflammatory disease    -   (i) according to 9a) to 9c), wherein the neutralizing antibody        or a functional fragment thereof specifically binding primate        GM-CSF is formulated for subcutaneous administration, or    -   (ii) according to any one of items 9d) to 9f), wherein the at        least one additional anti-inflammatory drug is methotrexate,        which is administered at a dose of 7.5 to 25 mg/weekly, e.g., at        a dose of 15-25 mg, or 7.5 to 15 mg/weekly, and wherein the        neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF is formulated for        subcutaneous administration,    -   and wherein in any of (i) or (ii) the first initial dose of said        neutralizing antibody or functional fragment thereof as well as        the second dose and optionally further doses comprises a        quantity of 20 mg, or of 80 mg, or of 150 mg,    -   and wherein in any of (i) or (ii) the pain is moderate, moderate        to severe or severe pain,    -   and wherein in any of (i) or (ii) the neutralizing antibody or a        functional fragment thereof specifically binding primate GM-CSF        comprising a light chain variable region set forth in SEQ ID No:        19 and a heavy chain variable region set forth in SEQ ID NO: 21,        or sequences that are at least 70%, at least 75%, at least 80%,        at least 85%, at least 90%, at least 95%, at least 97%, or at        least 99%, identical with SEQ ID NO: 19 and/or with SEQ ID NO:        21, e.g., a light chain amino acid sequence as set out in SEQ ID        NO: 34 and a heavy chain amino acid sequence as set out in any        of SEQ ID NOs: 35-48, e.g., SEQ ID NO: 35, or sequences that are        at least 70%, at least 75%, at least 80%, at least 85%, at least        90%, at least 95%, at least 97%, or at least 99%, identical with        SEQ ID NO: 34 and/or with SEQ ID NOs: 35-48, e.g., with SEQ ID        NO:35,    -   and wherein in any of (i) or (ii) the subject has moderate,        moderate to severe, or severe rheumatoid arthritis that is        insufficiently controlled by either methotrexate alone, or by        methotrexate in combination with at least one other chemical        DMARD(s) and/or at least one TNF-inhibitor.    -   9p) The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        an inflammatory disease    -   (i) according to any one of items 9 and 9a) to 9c), wherein the        neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF is formulated for        subcutaneous administration, or    -   (ii) according to any one of items 9d) to 9f), wherein the at        least one additional anti-inflammatory drug is methotrexate,        which is administered at a dose of 7.5 to 25 mg/weekly, e.g., at        a dose of 15-25 mg, or 7.5 to 15 mg/weekly, and wherein the        neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF is administered        subcutaneously,    -   and wherein in any of (i) or (ii) the first initial dose of said        neutralizing antibody or functional fragment thereof, as well as        the second dose and optionally further doses comprises a        quantity of 20 mg, or 80 mg, or 150 mg,    -   and wherein in any of (i) or (ii) the pain is moderate, moderate        to severe or severe pain, and wherein the neutralizing antibody        or a functional fragment thereof specifically binding primate        GM-CSF comprising a light chain variable region set forth in SEQ        ID No: 19 and a heavy chain variable region set forth in SEQ ID        NO: 21, or sequences that are at least 70%, at least 75%, at        least 80%, at least 85%, at least 90%, at least 95%, at least        97%, or at least 99%, identical with SEQ ID NO: 19 and/or with        SEQ ID NO: 21, a light chain amino acid sequence as set out in        SEQ ID NO: 34 and a heavy chain amino acid sequence as set out        in any of SEQ ID NOs: 35-48, e.g., SEQ ID NO: 35, or sequences        that are at least 70%, at least 75%, at least 80%, at least 85%,        at least 90%, at least 95%, at least 97%, or at least 99%,        identical with SEQ ID NO: 34 and/or with SEQ ID NOs: 35-48, with        SEQ ID NO:35,    -   and wherein in any of (i) or (ii) the subject has moderate,        moderate to severe, or severe rheumatoid arthritis that is        insufficiently controlled by either methotrexate alone, or by        methotrexate in combination with one TNF-inhibitor.    -   9q) The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        an inflammatory disease    -   (i) according to item any one of items 9 and 9a) to 9c), wherein        the neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF is formulated for        subcutaneous administration, or    -   (ii) according to any one of items 9d) to 9f), wherein the at        least one additional anti-inflammatory drug is methotrexate,        which is administered at a dose of 7.5 to 25 mg/weekly, e.g., at        a dose of 15-25 mg, or 7.5 to 15 mg/weekly, and wherein the        neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF is administered        subcutaneously,    -   and wherein in any of (i) or (ii) the first initial dose of said        neutralizing antibody or functional fragment thereof, as well as        the second dose and optionally further doses comprises a        quantity of 20 mg, or of 80 mg, or of 150 mg,    -   and wherein in any of (i) or (ii) the pain is moderate, moderate        to severe or severe pain,    -   and wherein in any of (i) or (ii) the neutralizing antibody or a        functional fragment thereof specifically binding primate GM-CSF        comprising a light chain variable region set forth in SEQ ID No:        19 and a heavy chain variable region set forth in SEQ ID NO: 21,        or sequences that are at least 70%, at least 75%, at least 80%,        at least 85%, at least 90%, at least 95%, at least 97%, or at        least 99%, identical with SEQ ID NO: 19 and/or with SEQ ID NO:        21, e.g., a light chain amino acid sequence as set out in SEQ ID        NO: 34 and a heavy chain amino acid sequence as set out in any        of SEQ ID NOs: 35-48, e.g., SEQ ID NO: 35, or sequences that are        at least 70%, at least 75%, at least 80%, at least 85%, at least        90%, at least 95%, at least 97%, or at least 99%, identical with        SEQ ID NO: 34 and/or with SEQ ID NOs: 35-48, e.g., with SEQ ID        NO:35,    -   and wherein in any of (i) or (ii) the subject has moderate,        moderate to severe, or severe rheumatoid arthritis that is        insufficiently controlled by either methotrexate alone, or by        methotrexate in combination with one TNF-inhibitor.    -   9r) The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        an inflammatory disease    -   (i) according to item any one of items 9 and 9a) to 9c), wherein        the neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF is formulated for        subcutaneous administration, or    -   (ii) according to any one of items 9d) to 9f), wherein the at        least one additional anti-inflammatory drug is methotrexate,        which is administered at a dose of 7.5 to 25 mg/weekly, e.g., at        a dose of 15-25 mg, or 7.5 to 15 mg/weekly, and wherein the        neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF is administered        subcutaneously,    -   and wherein in any of (i) or (ii) the first initial dose of said        neutralizing antibody or functional fragment thereof, as well as        the second dose and optionally further doses comprises a        quantity of 20 mg, or of 80 mg, or of 150 mg,    -   and wherein in any of (i) or (ii) the pain is moderate, moderate        to severe or severe pain,    -   and wherein in any of (i) or (ii) the neutralizing antibody or a        functional fragment thereof specifically binding primate GM-CSF        comprising a light chain variable region set forth in SEQ ID No:        19 and a heavy chain variable region set forth in SEQ ID NO: 21,        or sequences that are at least 70%, at least 75%, at least 80%,        at least 85%, at least 90%, at least 95%, at least 97%, or at        least 99%, identical with SEQ ID NO: 19 and/or with SEQ ID NO:        21, e.g., a light chain amino acid sequence as set out in SEQ ID        NO: 34 and a heavy chain amino acid sequence as set out in any        of SEQ ID NOs: 35-48, e.g., SEQ ID NO: 35, or sequences that are        at least 70%, at least 75%, at least 80%, at least 85%, at least        90%, at least 95%, at least 97%, or at least 99%, identical with        SEQ ID NO: 34 and/or with SEQ ID NOs: 35-48, e.g., with SEQ ID        NO:35,    -   and wherein in any of (i) or (ii) the subject has moderate,        moderate to severe, or severe rheumatoid arthritis that is        insufficiently controlled by either methotrexate alone, or by        methotrexate in combination with one TNF-inhibitor,    -   and wherein in any of (i) or (ii) the administration of the        neutralizing antibody or functional fragment alone or in a        combination therapy with methotrexate or another anti-folate        compound thereof induces ACR20/50/70 scores of ≥50%/20%/10% at        24 weeks in TNF non-responders, or ≥55%/30%/10% in methotrexate        non-responders.    -   9s) The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        an inflammatory disease    -   (i) according to item any one of items 9 and 9a) to 9c), wherein        the neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF is formulated for        subcutaneous administration, or    -   (ii) according to any one of items 9d) to 9f), wherein the at        least one additional anti-inflammatory drug is methotrexate,        which is administered at a dose of 7.5 to 25 mg/weekly, e.g., at        a dose of 15-25 mg, or 7.5 to 15 mg/weekly, and wherein the        neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF is administered        subcutaneously,    -   and wherein in any of (i) or (ii) the first initial dose of said        neutralizing antibody or functional fragment thereof, as well as        the second dose and optionally further doses comprises a        quantity of 20 mg, or of 80 mg, or of 150 mg,    -   and wherein in any of (i) or (ii) the pain is moderate, moderate        to severe or severe pain,    -   and wherein in any of (i) or (ii) the neutralizing antibody or a        functional fragment thereof specifically binding primate GM-CSF        comprising a light chain variable region set forth in SEQ ID No:        19 and a heavy chain variable region set forth in SEQ ID NO: 21,        or sequences that are at least 70%, at least 75%, at least 80%,        at least 85%, at least 90%, at least 95%, at least 97%, or at        least 99%, identical with SEQ ID NO: 19 and/or with SEQ ID NO:        21, e.g., a light chain amino acid sequence as set out in SEQ ID        NO: 34 and a heavy chain amino acid sequence as set out in any        of SEQ ID NOs: 35-48, e.g., SEQ ID NO: 35, or sequences that are        at least 70%, at least 75%, at least 80%, at least 85%, at least        90%, at least 95%, at least 97%, or at least 99%, identical with        SEQ ID NO: 34 and/or with SEQ ID NOs: 35-48, e.g., with SEQ ID        NO:35,    -   and wherein in any of (i) or (ii) the subject has moderate,        moderate to severe, or severe rheumatoid arthritis that is        insufficiently controlled by either methotrexate alone, or by        methotrexate in combination with one TNF-inhibitor,    -   and wherein in any of (i) or (ii) the disease activity        (DAS28CRP) at least 12 weeks subsequent to the start of        treatment, e.g., at least 24 weeks subsequent to the start of        treatment is reduced to a score of <3.2, e.g., <2.6.    -   10. The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        an inflammatory disease according to item 9 including any of        items 9a) to 9s),        -   wherein the neutralizing antibody or a functional fragment            thereof specifically binding primate GM-CSF is used            according to the following dosing scheme:            -   (i) a first initial dose,            -   (ii) followed by administration of a second dose after                about 14 days after the first initial dose,            -   (iii) at least one further dose administered after 28                days after said second dose,            -   (iv) optionally followed by further doses administered                within intervals of about 28 days, and        -   wherein the patients are selected from the following            subgroups:        -   a-1) Patients not treated for an inflammatory condition or            for inflammatory pain, further selected from            -   individuals with RA that have not previously been                treated for RA, or            -   individuals that have not previously been treated for RA                who were diagnosed as RA patients at least 6 months                prior to the first initial dose, at least 1 year prior                to the first initial dose, 2 years prior to the first                initial dose, 3 years prior to the first initial dose, 4                years prior to the first initial dose, or more than 5                years prior to the first initial dose, or        -   a-2) Patients treated for RA who have not received            medication for pain in addition to the treatment for RA,        -   a-3) Patients treated for an inflammatory condition,            selected from the group comprising rheumatoid arthritis,            SLE, psoriatic arthritis, ankylosing spondylitis, juvenile            idiopathic arthritis, and osteoarthritis selected from the            following subgroups:            -   patients receiving a non-biologic DMARD treatment, but                who have previously not been treated with biologics                (biologics treatment naïve),            -   patients receiving a treatment with anti-folate                compounds, e.g., methotrexate, or other DMARS and/or                glucocorticoids,            -   patients receiving a treatment with anti-folate                compounds, e.g., a stable dose of methotrexate at                about >15 mg/week for at least 12 weeks and who do not                suffer from neutropenia,            -   patients that are treated with methotrexate for at least                3 months, wherein said patients further receiving                folinic acid or folic acid on the days after                methotrexate administration, but not on the day when                methotrexate is administered,            -   patients that are treated with methotrexate but not                co-treated with adenosine receptor antagonists selected                from a group comprising theophylline and caffeine,            -   patients that are treated with methotrexate without any                signs of marrow suppression, said signs comprising                neutropenia, for at least 12 weeks after initial                administration of weekly doses of 7.5-25 mg per week,                e.g., after initial administration of weekly doses of                15-25 mg, or 7.5-15 mg per week,            -   Patients that are treated with methotrexate, which                having a genetic polymorphism in at least one                thymidylate synthase gene, the AICAR transformylase                gene, or the RFC1 gene;            -   patients without polymorphism at C677T in the MTHFR                (methylene tetrahydrofolate reductase gene),            -   patients with insufficiently controlled RA treated with                methotrexate for at least 3 months with moderate,                moderate to severe, or severe disease activity            -   patients with moderate, moderate to severe, or severe                disease activity insufficiently controlled RA treated                with methotrexate for at least 3 months in combination                with another non-biologic DMARD, e.g., an anti-folate                compound, e.g., methotrexate,            -   patients with insufficiently controlled RA treated with                DMARDs, e.g. selected from sulfasalazine, leflunomide or                hydroxychloroquine, for at least 3 months with moderate,                moderate to severe, or severe disease activity            -   patients selected from the group of individuals                receiving non-biologic DMARD treatment, e.g., treatment                with an anti-folate compound, e.g., treatment with                methotrexate, plus biologic treatment, wherein the                biologic treatment is selected from the group of                compounds comprising comprising            -   anti-cytokine antagonists selected from a group chemical                antagonists and antibodies or derivatives thereof,            -   cytokine receptor antagonists selected from a group                comprising chemical antagonists and antibodies or                derivatives thereof,            -   TNF-alpha neutralising agents selected from a group                comprising chemical neutralising agents and antibodies                or derivatives thereof,            -   IL-1 neutralising agents selected from a group                comprising chemical neutralising agents and antibodies                or derivatives thereof,            -   IL-6 neutralising agents selected from a group                comprising chemical neutralising agents and antibodies                or derivatives thereof, and            -   CD20 neutralising agents selected from a group                comprising chemical neutralising agents and antibodies                or derivatives thereof,            -   patients with insufficiently controlled RA treated with                methotrexate for at least 3 months in combination with a                biologic DMARD with moderate, moderate to severe, or                severe disease activity,        -   a-4) Patients treated for inflammatory pain comprising            individuals selected from the follow subgroups of patients:            -   patients treated for pain associated with a disease                other than rheumatoid arthritis, wherein said disease is                selected from autoimmune diseases, neuropathies, or                inflammatory diseases,            -   patients treated with methotrexate for at least 3 months                in combination with a biologic DMARD with                moderate/moderate to severe/severe disease activity,                wherein the inflammatory pain is insufficiently                controlled by the treatment            -   patients with a non-biologic DMARD treatment and                reduction of RA signs and symptoms and inhibition of                progression of structural damage,            -   wherein the pain persists or remits,            -   patients with no signs of ongoing inflammation, where                pain in the joints is still present,            -   patients insufficiently controlled on methotrexate,            -   patients who were insufficiently controlled on                methotrexate plus TNF alpha inhibitor treatment;            -   patients who were insufficiently controlled on treatment                with sulfasalazine, hydroxychloroquine, and/or                leflunomide or other DMARDS,            -   patients that do not suffer from neutropenia or a                cancer; or            -   patients that have not been treated with GM-CSF prior to                the first initial dose (t=d0);            -   patients that have previously not been treated to                correct chemotherapy induced cytopenias and to                counteract cytopenia-related predisposition to                infections and hemorrhages,            -   patients that do not suffer from respiratory tract                problems, particularly lung problems associated with                infections.    -   11. A neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        an inflammatory disease as defined in any one of items 1 to 10,        -   wherein the administration of the second dose is omitted,            thereby having the doses after the first initial dose            administered in intervals of 21-35 days, optionally about 28            days.    -   12. The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        an inflammatory disease as defined in any one of items 1 to 11,        wherein the antibody is formulated for subcutaneous        administration.    -   13. The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        an inflammatory disease as defined in any one of items 1 to 12,        wherein the first initial dose of said neutralizing antibody or        functional fragment thereof, as well as the second dose and        optionally further doses comprises a quantity of 10 to 50 mg, or        a quantity of 25 to 100 mg, or a quantity of 50 to 300 mg.    -   14. The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        an inflammatory disease as defined in any one of items 1 to 13,        wherein the first initial dose of said neutralizing antibody or        functional fragment thereof, as well as the second dose and        optionally further doses comprises a quantity of 20 mg, or of 80        mg, or of 150 mg.    -   15. The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        an inflammatory disease as defined in any one of items 1 to 14,        wherein said antibody comprises a light chain variable region        comprising an amino acid sequence as set out in SEQ ID NOs: 19,        34, 54 or 55, and a heavy chain variable region comprising an        amino acid sequence chosen from the group consisting of those        set out in any of the SEQ ID NOs: 20-33, 35-48, 52 or 53, e.g.,        said antibody comprises a light chain variable region comprising        an amino acid sequence as set out in SEQ ID NO: 19, and a heavy        chain variable region comprising an amino acid sequence set out        in any of the SEQ ID NOs: 21.    -   16. The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        an inflammatory disease as defined in any one of items 1 to 15,        wherein said neutralizing antibody or functional fragment        thereof comprises in its heavy chain variable region a CDR3        comprising an amino acid sequence chosen from the group        consisting of those set out in any of the SEQ ID NOs: 1-13 or        56.    -   17. The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        an inflammatory disease as defined in any one of items 1 to 16,        wherein said neutralizing antibody or functional fragment        thereof comprises a heavy chain variable region CDR3 sequence        set out in any of the amino acid sequences in SEQ ID NOs: 1-13        or 56 together with the heavy chain variable region CDR1        sequence set out in the amino acid sequence of SEQ ID NO: 14 and        heavy chain variable region CDR2 sequence set out in the amino        acid sequence of SEQ ID NO: 15.    -   18. The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        an inflammatory disease as defined in any one of items 1 to 17,        wherein said neutralizing antibody or functional fragment        thereof comprises in its light chain variable region a CDR1        comprising the amino acid sequence set out in SEQ ID NO: 16, a        CDR2 comprising the amino acid sequence set out in SEQ ID NO:        17, and a CDR3 comprising the amino acid sequence set out in SEQ        ID NO: 18.    -   19. The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        an inflammatory disease as defined in any one of items 1 to 18,        wherein said neutralizing antibody or functional fragment        thereof comprises in its light chain variable region a CDR1        comprising an amino acid sequence as set out in SEQ ID NO: 16, a        CDR2 having an amino acid sequence as set out in SEQ ID NO: 17        and a CDR3 having an amino acid sequence as set out in SEQ ID        NO: 18; and comprising in its heavy chain variable region a CDR1        region comprising an amino acid sequence as set out in SEQ ID        NO: 14, a CDR2 region having an amino acid sequence as set out        in SEQ ID NO: 15 and a CDR3 having an amino acid sequence as set        out in any of SEQ ID Nos: 1-13 or 56, e.g., SEQ ID No. 2.    -   20. The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        an inflammatory disease as defined in any one of items 1 to 19,        comprising a light chain amino acid sequence as set out in SEQ        ID NO: 34 and a heavy chain amino acid sequence as set out in        any of SEQ ID NOs: 35-48, e.g., SEQ ID NO: 35.    -   21. The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        an inflammatory disease as defined in any one of items 1 to 20,        wherein said neutralizing antibody or functional fragment        thereof comprises an amino acid sequence bearing at least 70%        homology to the respective amino acid sequence as set out in any        of SEQ ID NOs: 1-48 and/or 52-56.    -   22. The neutralizing antibody or a functional fragment thereof        specifically binding primate GM-CSF for use in the treatment of        an inflammatory disease as defined in any one of items 1 to 21,        wherein additionally at least one further analgesic compound is        used.    -   23. The neutralizing anti-primate GM-CSF antibody or functional        fragment thereof for use according to any one of items 1 to 22,        wherein the at least one further analgesic compound is selected        from the group comprising oral corticosteroids, e.g.,        prednisolone or codeine.    -   24. A method of treatment of an inflammatory disease selected        from a group comprising rheumatoid arthritis, SLE, psoriatic        arthritis, ankylosing spondylitis, juvenile idiopathic        arthritis, or osteoarthritis in a patient comprising        administering the neutralizing antibody or a functional fragment        thereof specifically binding primate GM-CSF as defined in any        one of items 1 to 23.    -   25. The method according to any one of item 24, wherein the        patient suffers from mild, mild to moderate, moderate, moderate        to severe or severe rheumatoid arthritis, e.g., moderate,        moderate to severe or severe rheumatoid arthritis.    -   26. The method according to any one of items 24 or 25, wherein        the subject has moderate, moderate to severe, or severe        rheumatoid arthritis that is insufficiently controlled by either        methotrexate alone, or by methotrexate in combination with at        least one other chemical DMARD(s) and/or at least one        TNF-inhibitor and/or at least one inhibitor of a cytokine        different from TNF, e.g. an IL-6R inhibitor.    -   27. The method according to any one of items 24 to 26, wherein        neutralizing antibody or functional fragment thereof is        administered parenterally, e.g., subcutaneously.    -   28. The method according to any one of items 24 to 27, wherein        the neutralizing antibody or functional fragment thereof as        defined in any of the preceding claims is administered        subcutaneously in at least 3, at least 5, at least 7 doses over        a period of at least 21 weeks.    -   29. The method according to any one of items 24 to 28, wherein        the administration of the neutralizing antibody or functional        fragment alone or in a combination therapy with methotrexate or        another anti-folate compound thereof induces ACR20/50/70 scores        of ≥50%/20%/10% at 24 weeks in TNF non-responders, or        ≥55%/30%/10% in methotrexate non-responders.    -   30. The method according to any one of items 24 to 29, wherein        the treatment alleviates fatigue and/or sleeping disturbances        associated with pain.    -   31. The method according to any one of items 24 to 30, wherein        the patient's pain symptoms remit for at least 1 year subsequent        to the start of treatment.    -   32. The method according to any one of items 24 to 31, wherein        structural joint damages does not advance for at least 1 year        subsequent to the start of treatment.    -   33. The method according to any one of items 24 to 32, wherein        the disease activity (DAS28CRP) at least 12 weeks subsequent to        the start of treatment, at least 24 weeks subsequent to the        start of treatment is reduced to a score of <3.2, e.g., <2.6.    -   34. The method according to any one of items 24 to 33, wherein        the serum levels contains at least 20%, at least 25%, at least        30%, at least 40%, at least 50% of the neutralizing anti-primate        GM-CSF antibody or functional fragment thereof seven days, for        at least 14 days, e.g., for at least 21 days, for at least 28        days after the last administration.

In any of the above embodiments it is contemplated to administer thefirst dose optionally as a so-called “loading dose” of the neutralizinganti-GM-CSF antibody, and preferably in an amount of two times theamount administered with the first dose according to the present dosingregime. For example, when the first dose according to the hereindisclosed dosing regimen (usually) comprises administration of 150 mg ofthe neutralizing antibody or functional fragment thereof, the loadingdose is administered in an amount of, preferably two times 150 mg.

Description of the Invention

The American College of Rheumatology (ACR) proposed a set of criteriafor classifying RA. The commonly used criteria are the ACR 1987 revisedcriteria. Diagnosis of RA according to the ACR criteria requires apatient to satisfy a minimum number of listed criteria, such as tenderor swollen joint counts, stiffness, pain, radiographic indications andmeasurement of serum rheumatoid factor. ACR 20, ACR 50 and ACR 70 arecommonly used measures to express efficacy of RA therapy, particularlyin clinical trials. ACR 20 represents a 20% improvement in the measuredACR criteria. Analogously, ACR 50 represents a 50% improvement in themeasured ACR criteria, and ACR 70 represents a 70% improvement in themeasured ACR criteria. In preferred embodiments of the presentinvention, the neutralizing antibody or functional fragments thereofachieve an ACR of at least 20, e.g., at least 30, e.g., at least 40, 50,60, or 70.

An individual, patient reported measure of disability in RA patients isthe Health Assessment Questionnaire Disability Index (HAQ-DI). HAQ-DIscores represent physical function in terms of the patient's reportedability to perform everyday tasks, including the level of difficultythey experience in carrying out the activity. By recording patients'ability to perform everyday activities, the HAQ-DI score can be used asone measure of their quality of life.

Clinical benefit achieved as described herein may comprise any one ormore of the following outcomes.

The clinical benefit may be a decrease in DAS28-CRP by more than 1.2.The reduction in DAS28-CRP may be achieved in at least 40%, at least 50%or at least 60% of patients treated. The clinical benefit may comprisean increasing the proportion of patients who achieve a decrease inDAS28-CRP by more than 1.2, compared with control patients who are nottreated with the neutralizing antibody or functional fragment thereof asused according to the invention.

The clinical benefit may comprise remission of RA. Typically, remissionis defined by a DAS28-CRP of less than 2.6. In patients treated asdescribed herein, the time to onset of remission may be reduced comparedwith patients who are not treated with a neutralizing antibody orfunctional fragment thereof according to the invention time to remissionmay be reduced. It is also of clinical benefit to achieve low diseaseactivity in those patients where remission is not achieved.

According to the present invention, the neutralizing antibody or afunctional fragment thereof specifically binding primate GM-CSF for usein the treatment of improves the radiographically measurable ACRcriteria, preferably the neutralizing antibody or functional fragmentsthereof achieve an ACR of at least 20, e.g., at least 30, e.g., at least40, 50, 60, or 70.

The clinical benefit of using the neutralizing antibody or functionalfragment thereof according to the invention may be an improvement of atleast 20%, at least 50% or at least 70% treatment efficacy as determinedby the 1987 ACR criteria, i.e. the clinical benefit may be achieving ACR20, ACR 50 or ACR 70, respectively. The clinical benefit comprisesachieving ACR 20 in at least 40, 50, 55, 60, 65 or 70% of patients. Itmay comprise achieving ACR 50 in at least 20, 25, 30, 35 or 40% ofpatients. It may comprise achieving ACR 70 in at least 5%, 10%, 15 or20% of patients with insufficiently controlled RA by MTX treatmentalone, or patients with insufficiently controlled RA by MTX treatmentand anti-TNF treatment.

A form of clinical benefit that is of particular value to RA patients isan improvement in their ability to perform everyday activities. Methodsof the invention may comprise improvement in the patient's self-assesseddisability measured by the Health Assessment Questionnaire, known asHAQ-DI. The following categories are assessed by the HAQ-DI: dressingand grooming, arising, eating, walking, hygiene, reach, grip, commondaily activities. The patients report the amount of difficulty they havein performing some of these activities. Each question asks on a scaleranging from 0 to 3 if the categories can be performed without anydifficulty (scale 0) up to cannot be done at all (scale 3) (Ramey D R,Fries J F, Singh G. The Health Assessment Questionnaire 1995-status andreview. In: Quality of Life and pharmacoeconomics in clinical trials.Second edition. Edited by B Spilker. Lippincott-Raven Publishers,Philadelphia, 1996). Methods comprising providing clinical benefit to anRA patient, wherein the clinical benefit comprises improving physicalfunction of an RA patient as determined by HAQ-DI, and compositions andkits for use in such methods, are all aspects of the invention. Clinicalbenefit may comprise improving physical function of an RA patient asdetermined by HAQ-DI. Preferably, a statistically significantimprovement in HAQ-DI is achieved within twelve, ten, eight or six weeksof starting treatment according to the invention, e.g., within fourweeks, or within two weeks. The improvement may be at least a 0.25improvement in HAQ-DI, i.e. a reduction of 0.25 or more in the patient'sHAQ-DI score. Preferably, the improvement is at least a 0.30, 0.40 or0.45 improvement in HAQ-DI score. Improvement is generally measured withreference to the patient's baseline average HAQ-DI score prior totreatment with an inhibitor according to the invention. Where a group ofpatients is treated, the improvement may be observed in at least 50%, atleast 60% or at least 70% of treated patients. The clinical benefit maybe achieved sooner in treated patients compared with patients who arenot treated with an inhibitor according to the invention. For example,patients who are treated with an inhibitor according to the invention incombination with methotrexate may achieve clinical benefit sooner thanpatients treated with methotrexate alone. The time to onset of response,or period of treatment before the clinical benefit is achieved, may bedecreased by at least 10%, at least 20%, at least 30%, at least 40% orat least 50% compared with patients who are not treated with theinhibitor. Preferably, the clinical benefit is achieved within 85 days.So, for example, DAS28-CRP may be decreased by more than 1.2 within 85days. More preferably, the onset of response occurs within 2 weeks.Thus, clinical benefit may be achieved within 14 days of treatment withthe neutralizing antibody according to the invention or functionalfragment thereof.

Patients may be monitored during and/or following a course of treatmentwith the inhibitor, to assess the level of clinical benefit, for exampleby measuring DAS28-CRP and/or determining clinical benefit according tothe ACR criteria and/or measuring HAQ-DI. The method may comprisedetermining that the clinical benefit is achieved, e.g. that thespecified reduction in DAS28-CRP, and/or achievement of ACR20, ACR50 orACR70 is met, and/or that the HAQ-DI score is improved.

According to the present invention, the neutralizing antibody or afunctional fragment thereof specifically binding primate GM-CSF for usein the treatment of pain emanating from an inflammatory disease, e.g.,RA, in a patient to provide clinical benefit as measured by a decreasein DAS28-CRP by more than 1.2 within 85 days, the method comprisingadministering a composition comprising the neutralizing antibody toGM-CSF or a functional fragment thereof to the patient, wherein thecomposition is administered at a dose of 20 mg or 50 mg or 80 mg or 150mg/month after two initial injections of the same dose on day d0 andabout 14 days later by subcutaneous administration.

In accordance with the present invention, the neutralizing antibody or afunctional fragment thereof specifically binding primate GM-CSF for usein the treatment of pain emanating from an inflammatory disease, e.g.,RA to provide clinical benefit as measured by an improvement of at leastACR50 or at least ACR70 within about 7 weeks, the method comprisingadministering a composition comprising the neutralizing antibody orfunctional fragment thereof to the patient, wherein the composition isadministered at a dose of 20 mg or of 50 mg or of 80 mg or of 150mg/month after two initial injections of the same dose on day d0 andabout 14 days later by parenteral, e.g., subcutaneous administration.

In accordance with the present invention, the neutralizing antibody or afunctional fragment thereof specifically binding primate GM-CSF for usein the treatment of pain emanating from an inflammatory disease, e.g.,RA for inducing remission of RA in a patient, as measured by a DAS28-CRPof less than 2.6, the method comprising administering a compositioncomprising a therapeutically effective amount of the neutralizingantibody or functional fragment thereof to the patient, wherein thecomposition is administered by subcutaneous administration, and whereinthe onset of remission is seen after about 12 weeks after the initialadministration of the neutralizing antibody or functional fragmentsdisclosed herein.

In accordance with the present invention, the neutralizing antibody or afunctional fragment thereof specifically binding primate GM-CSF for usein the treatment of pain emanating from an inflammatory disease, e.g.,RA, resulting in an improvement of physical function of an RA patient,as determined by HAQ-DI, is used in a method comprising administering acomposition comprising the neutralizing antibody or a functionalfragment thereof specifically binding GM-CSF to the patient, wherein thecomposition is administered in a dose of 10-150 mg, e.g., at a dose of10-30 mg, e.g., 20 mg, or at a dose of 50-150 mg, e.g., at a dose of 80mg, or at a dose of 100-300 mg, e.g., at a dose of 150 mg, in 1 mlmonthly by subcutaneous administration, and wherein an improvement inHAQ-DI is achieved within twelve weeks, e.g., wherein the improvement isa reduction of at least 0.25 in the patient's HAQ-DI score.

In accordance with the present invention, the methods according topresent invention for the treatment of subject having moderate, moderateto severe, or severe rheumatoid arthritis are specifically suited forpatients that are insufficiently controlled by either methotrexate (MTX)alone, or by MTX in combination with at least one other chemical DMARDand/or at least one TNF-inhibitor.

Within the context of the present invention, “Insufficiently controlledRA” means that a status of low disease activity (DAS28CRP≤3.2) is notreached or remission is not achieved (DAS28CRP<2.6) after about 12 weeksto 24 weeks. In additional feature may be, that also no inhibition ofprogression of joint destruction is identified on X-ray (only controlledafter ½ year and then every 1 year).

The patients to be treated according to the invention may have a mild,or mild to moderate, or a moderate, or a moderate to severe, or either asevere form of RA. In preferred embodiments of treatments of the presentinvention, the patients have moderate, moderate to severe or severedisease activity. These patients are generally older than 18 years, e.g.18 to 30 years of age, or 30 to 40 years old, or 40 to 50 years old, orolder than 50 years. In another embodiment, the patients may be juvenilepatients.

Based on the distribution of pain Visual analogue scores (VAS) inpostsurgical patients (knee replacement, hysterectomy, or laparoscopicmyomectomy) who described their postoperative pain intensity as none,mild, moderate, or severe, the following cut points on the pain VAS havebeen recommended: no pain (0-4 mm), mild pain (5-44 mm), moderate pain(45-74 mm), and severe pain (75-100 mm) (Jensen M P, Chen C, Brugger AM. Interpretation of visual analog scale ratings and change scores: areanalysis of two clinical trials of postoperative pain. J Pain 2003;4:407-14; Sokka T. Assessment of pain in rheumatic diseases. Clin ExpRheumatol. 2005 September-October; 23(5 Suppl 39):S77-84).

Patients may be monitored during and/or following a course of treatmentwith the inhibitor, to assess the level of VAS morning stiffnessseverity by Visual Analogue Scale (VAS) to evaluate Severity of morningstiffness on a 10-cm horizontal line with 0=none on the left and 10=verysevere on the right.

Measurement of morning stiffness in RA patients by a VAS for severitywas found to be a responsive endpoint measure. Especially in clinicaltrials in which the effects of a therapy directed toward reduction ofmorning stiffness are evaluated assessment of morning stiffness by meansof a VAS for severity appears to be a useful instrument. (Vliet VlielandT P, Zwinderman A H, Breedveld F C, Hazes J M. Measurement of morningstiffness in rheumatoid arthritis clinical trials. J Clin Epidemiol.1997 July; 50(7):757-63).

Patients may be monitored during and/or following a course of treatmentwith the inhibitor, to assess the level of VAS fatigue by a VisualAnalogue Scale to Evaluate Fatigue Severity (VAS-F) consists of 18 itemsrelated to fatigue and energy. Each line is 100 mm in length. Fatigue(items 1-5 and 11-18) and energy (items 6-10) (Hewlett S, Hehir M,Kirwan J R. Measuring fatigue in rheumatoid arthritis: a systematicreview of scales in use. Arthritis Rheum. 2007 Apr. 15; 57(3):429-39).

Patients may be monitored during and/or following a course of treatmentwith the inhibitor, to assess the level of neuropathic pain by using aNeuropathic pain questionnaire, the self-report version of the LeedsAssessment of Neuropathic Symptoms and Signs pain scale (S-LANSS:Bennett M I, Smith B H, Torrance N, Potter J. The S-LANSS score foridentifying pain of predominantly neuropathic origin: validation for usein clinical and postal research. J Pain. 2005 March; 6(3):149-58).

Insufficiently controlled pain means, that the pain associated with RAis not alleviated when the patient is treated either with MTX alone orwith MTX in combination with other chemical DMARDs or one TNF inhibitor.

The invention relates to the treatment of pain in connection withinflammatory and degenerative joint diseases selected from the listcomprising, rheumatoid arthritis, SLE, psoriatic arthritis, ankylosingspondylitis, juvenile idiopathic arthritis, or osteoarthritis, includingmusculoskeletal and also neuropathic pain. Neuropathic pain may bepresent in patients with any of the above indications in the absence ofconcomitant signs of inflammation.

It is contemplated that the present methods and compositions may beemployed for the treatment of pain from chronic conditions (includinginhibiting progression of and/or reversing damage associated withchronic conditions). Chronic conditions include, for example, arthriticconditions such as osteoarthritis, rheumatoid arthritis, and psoriaticarthritis. For example, the present methods and compositions may be usedto treat one or more symptoms or signs of osteoarthritis of the joint,(such as a hip or knee) or the back (for example, the lower back).Chronic conditions also include, for example, conditions associated withor resulting from pain such as chronic pain, including pain associatedwith or arising from cancer, from infection or from the nervous system(e.g., neurogenic pain such as peripheral neurogenic pain followingpressure upon or stretching of a peripheral nerve or root or having itsorigin in stroke, multiple sclerosis or trauma, including of the spinalcord). Chronic conditions also include, for example, conditionsassociated with or arising from psychogenic pain (e.g., pain not due topast disease or injury or visible sign of damage inside or outside thenervous system). The present methods and compositions may also beemployed for the treatment of back pain from other arthritic conditions,including gout and spondylarthropathies (including ankylosingspondylitis, Reiter's syndrome, psoriatic arthropathy, enteropathicspondylitis, juvenile arthropathy or juvenile ankylosing spondylitis,and reactive arthropathy).

The present methods and compositions may be used for the treatment ofback pain from infectious or post-infectious arthritis (includinggonoccocal arthritis, tuberculous arthritis, viral arthritis, fungalarthritis, syphilitic arthritis, and Lyme disease).

In further preferred embodiments of the methods of the presentinvention, the treatment alleviates fatigue and/or sleeping disturbancesassociated with pain (as determined using the MOS sleep scale or anyother suitable scale). Intended to assess the extent of sleep problems,the MOS Sleep Scale measures six dimensions of sleep, includinginitiation, maintenance (e.g. staying asleep), quantity, adequacy,somnolence (e.g. drowsiness), and respiratory impairments (e.g.shortness of breath, snoring) (Hays R D, Stewart A L. Sleep measures. InStewart A L & Ware J E. (eds.), Measuring Functioning and Well-being:The Medical Outcomes Study Approach. Durham, N.C.: Duke UniversityPress, 1992, pp. 235-259).

In accordance with the methods of the present invention, the patient'smean pain experience is reduced for at least 1 year subsequent to thestart of treatment (as determined by the patient using the Mean Changein VAS pain).

In accordance with the methods of the present invention, structuraljoint damages do not advance for at least 1 year subsequent to the startof treatment as determined using X-ray to determine the erosion score orthe joint space narrowing compared with the corresponding parametersbefore the start of the inventive treatment.

In accordance with the methods of the present invention, the diseaseactivity (DAS28-CRP) after at least 12 weeks subsequent to the start oftreatment, e.g., at least 24 weeks subsequent to the start of treatmentis reduced.

Primary Efficacy Values:

DAS28-CRP

-   -   CRP, C-reactive protein to be measured in serum    -   Tender joints counts (TJC) 28 joints    -   Swollen joints counts (SJC) 28 joints    -   VAS Patients global assessment disease activity on a visual        analog scale

In accordance with the methods of the present invention, the serumlevels contains 50% of the anti-primate GM-CSF antibody or functionalfragment thereof at least 7 days, at least 14 days, at least 21 days,e.g., at least 28 days after the last administration of an compositioncomprising the neutralizing antibody or functional fragment thereofaccording to the invention. Generally, the serum contains about 50% ofthe anti-primate GM-CSF antibody or functional fragment thereof at 28days after the last administration. Preferably, the serum contains 50%of the anti-primate GM-CSF antibody or functional fragment thereof at 21days after the last administration. The half-life of the anti-primateGM-CSF antibody may be at least 21 days, or at least about 25 days orlonger.

In accordance with the methods of the present invention, the methods thetreatment alleviate pain-associated fatigue and/or sleeping disturbancesdetermined as VAS fatigue on the MOS sleep scale.

In accordance with the methods of the present invention, the methods thepatient's pain symptoms remit for at least 1 year subsequent to thestart of treatment.

In accordance with the methods of the present invention, the methodsstructural joint damages do not advance for at least 1 year subsequentto the start of treatment.

In accordance with the methods of the present invention, the diseaseactivity (DAS28CRP) after at least 12 weeks subsequent to the start oftreatment, e.g., at least 24 weeks subsequent to the start of treatmentis reduced.

In further embodiments, the following clinical parameters may bemeasured: ePRO tool instruction, ePRO VAS pain; VAS Fatigue, VAS morningstiffness; S-LANSS Score; Neuropathic pain questionnaire; Joint-X ray,RAID+flare questions, SF-36v2. These PRO will be assessed daily toinvestigate effect on pain (with the exception of X-ray, Raid andSF-36).

In accordance with the methods of the present invention, the treatmentof pain comprises the subcutaneous administration of the above-describedanalgesic compositions or neutralizing antibody or functional fragmentthereof. The analgesic compositions, or the neutralizing antibody orfunctional fragments thereof of the present invention may beadministered subcutaneously in the inventive methods of treatment ofpain, e.g. at doses of 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg,80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg,170 mg, 180 mg, 190 mg, 200 mg, 225 mg, 250 mg, 275 mg, of 300 mg, orhigher. It is preferred that the analgesic compositions, or theneutralizing antibody or functional fragments thereof of the presentinvention is administered subcutaneously at doses of 10 mg, 20 mg, 30mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg,130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 225 mg,250 mg, 275 mg, of 300 mg, in at least 3, e.g., at least 5, e.g., atleast 7 doses over a period of at least 21 weeks. It is, however,possible to administer fewer or more of doses according to the specificrequirements and the patient's characteristics (e.g. depending onseverity of disease, gender, age, weight, other drugs used, etc.). Theduration of the treatment may be at least 21 weeks, but it iscontemplated that the therapeutic methods of the invention are set forthas long as necessary. It is also contemplated that MTX is administeredat the same time according to standard therapeutic regimen (e.g. 7.5 mgto 25 mg MTX per week as suggested in the Guidelines of the BritishSociety for Rheumatology of July 2000), e.g., at a dose of 7.5 to 15mg/week.

It is also possible to administer the herein disclosed analgesiccompositions of the neutralizing antibody or functional fragmentsthereof for any of the above time periods, but with intervals, e gadminister the compositions or active ingredients for 2, 3, or 4 weeksor 1, 2, or 3 months and use an interval of 2, 3, or 4 weeks or 1, 2, or3 months, where no analgesic composition is administered. At the sametime, administration of MTX at the above indicated weekly doses shouldbe continued, optionally accompanied by supplementary administration offolic acid/folinic acid on the days where MTX is not administered.

In accordance with the methods of the present invention, theneutralizing antibodies against GM-CSF or functional fragments thereofare administered according to regimens set forth in the appended claims.

In accordance with the methods of the present invention, administrationof any of the herein disclosed analgesic compositions, or of theneutralizing antibody or functional fragments thereof in apharmaceutically acceptable carrier, e.g., in a pharmaceuticallyacceptable carrier that allows for subcutaneous administration iscontemplated. In accordance with the methods of the present invention,administration of the analgesic composition or neutralizing antibody orfunctional fragment thereof results in an about ≥20%, about ≥25%, about≥30%, ≥40%, or about ≥50% reduction of pain as measured on the 100 mmVAS scale after 12 weeks.

In accordance with the methods of the present invention, administrationof the analgesic composition or neutralizing antibody or functionalfragment thereof results in an about ≥20 points, about ≥25 points, about≥30 points, about ≥40 points, or about >50 points reduction of painaccording to the 100 mm VAS scale after 12 weeks.

In accordance with the methods of the present invention, administrationof the analgesic composition or neutralizing antibody or functionalfragment thereof results in an in vivo half-life of the activeingredient of about 2 to 6 weeks, e.g. about 3 to 4 weeks afteradministration to the patient.

Accordingly one aspect of the invention relates to a human monoclonalantibody or functional fragment thereof which specifically binds to andneutralizes primate GM-CSF.

The term “specifically binds” or related expressions such as “specificbinding”, “binding specifically”, “specific binder” etc. as used hereinrefer to the ability of the human monoclonal antibody or functionalfragment thereof to discriminate between primate GM-CSF and any numberof other potential antigens different from primate GM-CSF to such anextent that, from a pool of a plurality of different antigens aspotential binding partners, only primate GM-CSF is bound, or issignificantly bound. Within the meaning of the invention, primate GM-CSFis “significantly” bound when, from among a pool of a plurality ofequally accessible different antigens as potential binding partners,primate GM-CSF is bound at least 10-fold, e.g., 50-fold, e.g., 100-foldor greater more frequently (in a kinetic sense) than any other antigendifferent than primate GM-CSF. Such kinetic measurements can beperformed on a Biacore apparatus.

As used herein, “neutralization,” “neutralizer,” “neutralizing” andgrammatically related variants thereof refer to partial or completeattenuation of the biological effect(s) of GM-CSF. Such partial orcomplete attenuation of the biological effect(s) of GM-CSF results frommodification, interruption and/or abrogation of GM-CSF-mediated signaltransduction, as manifested, for example, in altering activation ofcells, e.g. neurons, in particular nociceptive neurons, intracellularsignaling, cellular proliferation or release of soluble substances, up-or down-regulation of intracellular gene activation, for example thatresulting in expression of surface receptors for ligands other thanGM-CSF. As one of skill in the art understands, there exist multiplemodes of determining whether an agent, for example an antibody inquestion or functional fragment thereof is to be classified as aneutralizer. As an example, this may be accomplished by a standard invitro test performed generally as follows: In a first proliferationexperiment, a cell line, the degree of proliferation of which is knownto depend on the activity of GM-CSF, is incubated in a series of sampleswith varying concentrations of GM-CSF, following which incubation thedegree of proliferation of the cell line is measured. From thismeasurement, the concentration of GM-CSF allowing half-maximalproliferation of the cells is determined. A second proliferationexperiment is then performed employing in each of a series of samplesthe same number of cells as used in the first proliferation experiment,the above-determined concentration of GM-CSF and, this time, varyingconcentrations of an antibody or functional fragment thereof suspectedof being a neutralizer of GM-CSF. Cell proliferation is again measuredto determine the concentration of antibody or functional fragmentthereof sufficient to effect half-maximal growth inhibition. If theresulting graph of growth inhibition vs. concentration of antibody (orfunctional fragment thereof) is sigmoid in shape, resulting in decreasedcell proliferation with increasing concentration of antibody (orfunctional fragment thereof), then some degree of antibody-dependentgrowth inhibition has been effected, i.e. the activity of GM-CSF hasbeen neutralized to some extent. In such a case, the antibody orfunctional fragment thereof may be considered a “neutralizer” in thesense of the present invention. One example of a cell line, the degreeof proliferation of which is known to depend on the activity of GM-CSF,is the TF-1 cell line, as described in Kitamura, T. et al. (1989). JCell Physiol 140, 323-34. As one of ordinary skill in the artunderstands, the degree of cellular proliferation is not the onlyparameter by which neutralizing capacity may be established. Forexample, measurement of the level of signaling molecules (e.g.cytokines), the level of secretion of which depends on GM-CSF, may beused to identify a suspected GM-CSF neutralizer.

Other examples of cell lines which can be used to determine whether anantibody in question or functional fragment thereof is a neutralizer ofprimate GM-CSF activity include AML-193 (Lange, B. et al (1987). Blood70, 192-9); GF-D8 (Rambaldi, A. et al (1993). Blood 81, 1376-83); GM/SO(Oez, S. et al (1990). Experimental Hematology 18, 1108-11); M07E(Avanzi, G. C. et al. (1990). Journal of Cellular Physiology 145,458-64); TALL-103 (Valtieri, M. et al. (1987). Journal of Immunology138, 4042-50); UT-7 (Komatsu, N. et al (1991). Cancer Research 51,341-8).

As used herein, DMARDs (disease-modifying anti-rheumatic drugs)designates a group of synthetic drugs (not biologics) which areconventionally used in the treatment of RA to slow down diseaseprogression. Often, the term is used to distinguish drugs fromnon-steroidal anti-inflammatory drugs and steroids. Examples of DMARD,anti-folate compounds such as methotrexate (MTX), hydroxychloroquine,auranophine, azathioprine, chloroquine, ciclosporin A, D-penicillamine,leflunomide, minocycline, sulfasalzine, and others. According to theinvention, MTX is the DMARD generally used in combination therapy withthe herein described neutralizing antibodies or functional fragmentsthereof of GM-CSF.

As used herein, the term “biologics” designates drugs that have beenproduced using biotechnological methods, e.g. therapeutic antibodiessuch as adalimumab, etanercept, golimumab, infliximab, and others.

As used herein, the term “TNF inhibitor” designates a biological drugthat specifically targets TNFα or a receptor of TNFα. Drugs targetingTNF are for example the above-mentioned adalimumab, etanercept,golimumab, or infliximab.

Furthermore, it is also possible to use other biologics in combinationwith the analgesic compositions of the present invention, for examplemonoclonal antibodies targeting CD20, for example rituximab, orantibodies targeting other cytokines or cytokine receptors, for exampletocilizumab, which targets the IL-6 receptor, or antibodies targetingthe GM-CSF-receptor, anti-IL 17.

Pain may be analyzed in various animal models (J. S. Mogil, NatureReviews Neuroscience, 2009, April 10(4): 283-294). The activity ofrodent antibodies targeting GM-CSF was analyzed in mice withexperimentally induced osteoarthritis (WO2010/071923). In contrast tothe rodent antibodies used in animals in the osteoarthritis model, thehuman antibody or functional fragment thereof according to the inventionis monoclonal. As used herein, the term “monoclonal” is to be understoodas having the meaning typically ascribed to it in the art, namely anantibody (or its corresponding functional fragment) arising from asingle clone of an antibody-producing cell such as a B cell, andrecognizing a single epitope on the antigen bound.

It is particularly difficult to prepare human antibodies which aremonoclonal. In contrast to fusions of murine B cells with immortalizedcell lines, fusions of human B cells with immortalized cell lines arenot viable. Thus, the human monoclonal antibody of the invention is theresult of overcoming significant technical hurdles generallyacknowledged to exist in the field of antibody technology. Themonoclonal nature of the antibody makes it particularly well suited foruse as a therapeutic agent, since such antibody will exist as a single,homogeneous molecular species which can be well-characterized andreproducibly made and purified. These factors result in a product whosebiological activity can be predicted with a high level of precision,very important if such a molecule is going to gain regulatory approvalfor therapeutic administration in humans.

It is especially important that the monoclonal antibody (orcorresponding functional fragment) according to the invention be a humanantibody (or corresponding functional fragment). In contemplating anantibody agent intended for therapeutic administration to humans, it ishighly advantageous that this antibody is of human origin. Followingadministration to a human patient, a human antibody or functionalfragment thereof will most probably not elicit a strong immunogenicresponse by the patient's immune system, i.e. will not be recognized asbeing a “foreign”, that is non-human protein. This means that no host,i.e. patient antibodies will be generated against the therapeuticantibody which would otherwise block the therapeutic antibody's activityand/or accelerate the therapeutic antibody's elimination from the bodyof the patient, thus preventing it from exerting its desired therapeuticeffect.

The term “human” antibody as used herein is to be understood as meaningthat the antibody of the invention, or its functional fragment,comprises (an) amino acid sequence(s) contained in the human germ lineantibody repertoire. For the purposes of definition herein, an antibody,or its functional fragment, may therefore be considered human if itconsists of such (a) human germ line amino acid sequence(s), i.e. if theamino acid sequence(s) of the antibody in question or functionalfragment thereof is (are) identical to (an) expressed human germ lineamino acid sequence(s). An antibody or functional fragment thereof mayalso be regarded as human if it consists of (a) sequence(s) thatdeviate(s) from its (their) closest human germ line sequence(s) by nomore than would be expected due to the imprint of somatic hypermutation. Additionally, the antibodies of many non-human mammals, forexample rodents such as mice and rats, comprise VH CDR3 amino acidsequences which one may expect to exist in the expressed human antibodyrepertoire as well. Any such sequence(s) of human or non-human originwhich may be expected to exist in the expressed human repertoire wouldalso be considered “human” for the purposes of the present invention.

In accordance with the present invention, the primate GM-CSF is human(Homo sapiens) GM-CSF or non-human primate GM-CSF. Especially preferredvariants of non-human primate GM-CSF include gibbon monkey (Nomascusconcolor, also known as the western black crested gibbon) GM-CSF andGM-CSF of monkeys of the macaca family, for example rhesus monkey(Macaca mulatta) GM-CSF and cynomolgous monkey (Macaca fascicularis)GM-CSF. According to this embodiment of the invention, the humanmonoclonal antibody or functional fragment thereof exhibits crossreactivity between both human and at least one of the monkey speciesmentioned above. This is especially advantageous for an antibodymolecule which is intended for therapeutic administration in humansubjects, since such an antibody will normally have to proceed through amultitude of tests prior to regulatory approval, of which certain earlytests involve non-human animal species. In performing such tests, it isgenerally desirable to use as a non-human species a species bearing ahigh degree of genetic similarity to humans, since the results soobtained will generally be highly predictive of corresponding resultswhich may be expected when administering the same molecule to humans.However, such predictive power based on animal tests depends at leastpartially on the comparability of the molecule, and is very high when,due to cross-species reactivity, the same therapeutic molecule may beadministered to humans and animal models. As in this embodiment of theinvention, when an antibody molecule is cross reactive for the sameantigen in humans as in another closely related species, tests may beperformed using the same antibody molecule in humans as in this closelyrelated species, for example in one of the monkey species mentionedabove. This increases both the efficiency of the tests themselves aswell as predictive power allowed by such tests regarding the behavior ofsuch antibodies in humans, the ultimate species of interest from atherapeutic standpoint.

In accordance with the present invention, the human monoclonal antibodymay be an IgG antibody. As is well known in the art, an IgG comprisesnot only the variable antibody regions responsible for the highlydiscriminative antigen recognition and binding, but also the constantregions of the heavy and light antibody polypeptide chains normallypresent in endogenously produced antibodies and, in some cases, evendecoration at one or more sites with carbohydrates. Such glycosylationis generally a hallmark of the IgG format, and portions of theseconstant regions make up the so called Fc region of a full antibodywhich is known to elicit various effector functions in vivo. Inaddition, the Fc region mediates binding of IgG to Fc receptor, henceprolonging half life in vivo as well as facilitating homing of the IgGto locations with increased Fc receptor presence. Advantageously, theIgG antibody is an IgG1 antibody or an IgG4 antibody, formats which arepreferred since their mechanism of action in vivo is particularly wellunderstood and characterized. This is especially the case for IgG1antibodies.

In accordance with the present invention, the functional fragment of thehuman monoclonal antibody may be an scFv, a single domain antibody, anFv, a VHH antibody, a diabody, a tandem diabody, a Fab, a Fab′ or aF(ab)₂. These formats may generally be divided into two subclasses,namely those which consist of a single polypeptide chain, and thosewhich comprise at least two polypeptide chains. Members of the formersubclass include an scFv (comprising one VH region and one VL regionjoined into a single polypeptide chain via a polypeptide linker); asingle domain antibody (comprising a single antibody variable region)such as a VHH antibody (comprising a single VH region). Members of thelatter subclass include an Fv (comprising one VH region and one VLregion as separate polypeptide chains which are non-covalentlyassociated with one another); a diabody (comprising two non-covalentlyassociated polypeptide chains, each of which comprises two antibodyvariable regions—normally one VH and one VL per polypeptide chain—thetwo polypeptide chains being arranged in a head-to-tail conformation sothat a bivalent antibody molecule results); a tandem diabody (bispecificsingle-chain Fv antibodies comprising four covalently linkedimmunoglobulin variable—VH and VL—regions of two differentspecificities, forming a homodimer that is twice as large as the diabodydescribed above); a Fab (comprising as one polypeptide chain an entireantibody light chain, itself comprising a VL region and the entire lightchain constant region and, as another polypeptide chain, a part of anantibody heavy chain comprising a complete VH region and part of theheavy chain constant region, said two polypeptide chains beingintermolecularly connected via an interchain disulfide bond); a Fab′ (asa Fab, above, except with additional reduced disulfide bonds comprisedon the antibody heavy chain); and a F(ab)₂ (comprising two Fab′molecules, each Fab′ molecule being linked to the respective other Fab′molecule via interchain disulfide bonds). In general, antibodyfunctional fragments of the type described hereinabove allow greatflexibility in tailoring, for example, the pharmacokinetic properties ofan antibody desired for therapeutic administration to the particularexigencies at hand. For example, it may be desirable to reduce the sizeof the antibody administered in order to increase the degree of tissuepenetration when treating tissues known to be poorly vascularized (forexample, joints). Under some circumstances, it may also be desirable toincrease the rate at which the therapeutic antibody is eliminated fromthe body, said rate generally being accelerable by decreasing the sizeof the antibody administered.

According to the invention, said human monoclonal antibody or functionalfragment thereof may be present in monovalent monospecific; multivalentmonospecific, in particular bivalent monospecific; or multivalentmultispecific, in particular bivalent bispecific forms. In general, amultivalent monospecific, in particular bivalent monospecific antibodysuch as a full human IgG as described hereinabove may bring with it thetherapeutic advantage that the neutralization effected by such anantibody is potentiated by avidity effects, i.e. binding by the sameantibody to multiple molecules of the same antigen, here primate GM-CSF.Several monovalent monospecific forms or functional fragments of theantibody of the invention have been described above (for example, anscFv, an Fv, a VHH or a single domain antibody). Multivalentmultispecific, in particular bivalent bispecific forms of the humanmonoclonal anti-primate GM-CSF antibody of the invention may include afull IgG in which one binding arm binds to primate GM-CSF while theother binding arm of which binds to another antigen different fromprimate GM-CSF. A further multivalent multispecific, in particularbivalent bispecific form may advantageously be a human single chainbispecific antibody, i.e. a recombinant human antibody constructcomprising two scFv entities as described above, connected into onecontiguous polypeptide chain by a short interposed polypeptide spacer asgenerally known in the art (see for example WO 99/54440 for ananti-CD19×anti-CD3 bispecific single chain antibody). Here, one scFvportion of the bispecific single chain antibody comprised within thebispecific single chain antibody will specifically bind primate GM-CSFas set out above, while the respective other scFv portion of thisbispecific single chain antibody will bind another antigen determined tobe of therapeutic benefit.

In accordance with the present invention, the human monoclonal antibodyor functional fragment thereof may be derivatized, for example with anorganic polymer, for example with one or more molecules of polyethyleneglycol (“PEG”) and/or polyvinyl pyrrolidone (“PVP”). As is known in theart, such derivatization can be advantageous in modulating thepharmacodynamic properties of antibodies or functional fragmentsthereof. Especially preferred are PEG molecules derivatized asPEG-maleimide, enabling conjugation with the antibody or functionalfragment thereof in a site-specific manner via the sulfhydryl group of acysteine amino acid. Of these, especially preferred are 20 kD and/or 40kD PEG-maleimide, in either branched or straight-chain form. It may beespecially advantageous to increase the effective molecular weight ofsmaller human anti-primate GM-CSF antibody functional fragments such asscFv functional fragments by coupling the latter to one or moremolecules of PEG, especially PEG-maleimide.

In accordance with the present invention, the human monoclonal antibodyor functional fragment thereof specifically binds to an epitope, inparticular to a discontinuous epitope, of human or non-human primateGM-CSF comprising amino acids 23-27 (RRLLN) (SEQ ID NO: 57) and/or aminoacids 65-77 (GLR/QGSLTKLKGPL) (SEQ ID NO: 58).

The variability at position 67 within the amino acid sequence stretch65-77 depicted above reflects the heterogeneity in this portion ofprimate GM-CSF between, on the one hand, human and gibbon GM-CSF (inwhich position 67 is R) and, on the other hand, monkeys of the macacafamily, for example cynomolgous and rhesus monkeys (in which position 67is Q).

As used herein, the numbering of human and non-human primate GM-CSFrefers to that of mature GM-CSF, i.e. GM-CSF without its 17 amino acidsignal sequence (the total length of mature GM-CSF in both human andnon-human primate species described above is 127 amino acids). Thesequence of human GM-CSF and gibbon GM-CSF is as follows:

(SEQ ID NO: 49) APARSPSPST QPWEHVNAIQ EA RRLLN LSR D TAAEMNETVEVISEMFDLQ EPTCLQTRLE LYKQGLRGSL TKLKGPLTMMASHYKQHCPP TPETSCATQI ITFESFKENL KDFLLVIPFD CWEPVQE. 

The sequence of GM-CSF in certain members of the macaca monkey familysuch as for example rhesus monkey and cynomolgous monkey is as follows:

(SEQ ID NO: 50) APARSPSPGT QPWEHVNAIQ EA RRLLN LSR D TAAEMNKTVEVVSEMFDLQ EPSCLQTRLE LYKQGLQGSL TKLKGPLTMMASHYKQHCPP TPETSCATQI ITFQSFKENL KDFLLVIPFD CWEPVQE.

The minimum epitope, advantageously a discontinuous epitope, bound bythe human monoclonal antibody of the invention (or functional fragmentthereof) as described above is indicated in the above GM-CSF sequence inboldface. As used herein, the term “discontinuous epitope” is to beunderstood as at least two non-adjacent amino acid sequence stretcheswithin a given polypeptide chain, here mature human and non-humanprimate GM-CSF, which are simultaneously and specifically (as definedabove) bound by an antibody. According to this definition, suchsimultaneous specific binding may be of the GM-CSF polypeptide in linearform. Here, one may imagine the mature GM-CSF polypeptide forming anextended loop, in one region of which the two sequences indicated inboldface above line up, for example more or less in parallel and inproximity of one another. In this state they are specifically andsimultaneously bound by the antibody functional fragment of theinvention. According to this definition, simultaneous specific bindingof the two sequence stretches of mature GM-CSF indicated above may alsotake the form of antibody binding to a conformational epitope. Here,mature GM-CSF has already formed its tertiary conformation as itnormally exists in vivo (Sun, H. W., J. Bernhagen, et al. (1996). ProcNatl Acad Sci USA 93, 5191-6). In this tertiary conformation, thepolypeptide chain of mature GM-CSF is folded in such a manner as tobring the two sequence stretches indicated above into spatial proximity,for example on the outer surface of a particular region of mature,folded GM-CSF, where they are then recognized by virtue of theirthree-dimensional conformation in the context of the surroundingpolypeptide sequences.

In accordance with the present invention, the above (discontinuous)epitope further comprises amino acids 28-31 (LSRD), italicized in theabove sequences of human and non-human primate GM-CSF. In an especiallypreferred embodiment, either of the above (discontinuous) epitopesfurther comprises amino acids 32-33 (TA) and/or amino acids 21-22 (EA),each of which stretch is underlined in the above sequences of human andnon-human primate GM-CSF.

In accordance with the present invention, the human monoclonal antibodyor functional fragment thereof, or compositions or medicaments accordingto the invention comprising such antibodies or functional fragments,comprise in its heavy chain variable region a CDR3 comprising an aminoacid sequence chosen from the group consisting of those set out in anyof the SEQ ID NOs: 1-13 or 56. Preferred is a human monoclonal antibodyor functional fragment thereof comprising a heavy chain variable regionCDR1 sequence as set out in SEQ ID NO: 14, a heavy chain variable regionCDR2 sequence as set out in SEQ ID NO: 15 and a heavy chain variableregion CDR3 sequence as set out in SEQ ID NO: 1; or comprising a heavychain variable region CDR1 sequence as set out in SEQ ID NO: 14, a heavychain variable region CDR2 sequence as set out in SEQ ID NO: 15 and aheavy chain variable region CDR3 sequence as set out in SEQ ID NO: 2; orcomprising a heavy chain variable region CDR1 sequence as set out in SEQID NO: 14, a heavy chain variable region CDR2 sequence as set out in SEQID NO: 15 and a heavy chain variable region CDR3 sequence as set out inSEQ ID NO: 3; or comprising a heavy chain variable region CDR1 sequenceas set out in SEQ ID NO: 14, a heavy chain variable region CDR2 sequenceas set out in SEQ ID NO: 15 and a heavy chain variable region CDR3sequence as set out in SEQ ID NO: 4; or comprising a heavy chainvariable region CDR1 sequence as set out in SEQ ID NO: 14, a heavy chainvariable region CDR2 sequence as set out in SEQ ID NO: 15 and a heavychain variable region CDR3 sequence as set out in SEQ ID NO: 5; orcomprising a heavy chain variable region CDR1 sequence as set out in SEQID NO: 14, a heavy chain variable region CDR2 sequence as set out in SEQID NO: 15 and a heavy chain variable region CDR3 sequence as set out inSEQ ID NO: 6; or comprising a heavy chain variable region CDR1 sequenceas set out in SEQ ID NO: 14, a heavy chain variable region CDR2 sequenceas set out in SEQ ID NO: 15 and a heavy chain variable region CDR3sequence as set out in SEQ ID NO: 7; or comprising a heavy chainvariable region CDR1 sequence as set out in SEQ ID NO: 14, a heavy chainvariable region CDR2 sequence as set out in SEQ ID NO: 15 and a heavychain variable region CDR3 sequence as set out in SEQ ID NO: 8; orcomprising a heavy chain variable region CDR1 sequence as set out in SEQID NO: 14, a heavy chain variable region CDR2 sequence as set out in SEQID NO: 15 and a heavy chain variable region CDR3 sequence as set out inSEQ ID NO: 9; or comprising a heavy chain variable region CDR1 sequenceas set out in SEQ ID NO: 14, a heavy chain variable region CDR2 sequenceas set out in SEQ ID NO: 15 and a heavy chain variable region CDR3sequence as set out in SEQ ID NO: 10; or comprising a heavy chainvariable region CDR1 sequence as set out in SEQ ID NO: 14, a heavy chainvariable region CDR2 sequence as set out in SEQ ID NO: 15 and a heavychain variable region CDR3 sequence as set out in SEQ ID NO: 11; orcomprising a heavy chain variable region CDR1 sequence as set out in SEQID NO: 14, a heavy chain variable region CDR2 sequence as set out in SEQID NO: 15 and a heavy chain variable region CDR3 sequence as set out inSEQ ID NO: 12; or comprising a heavy chain variable region CDR1 sequenceas set out in SEQ ID NO: 14, a heavy chain variable region CDR2 sequenceas set out in SEQ ID NO: 15 and a heavy chain variable region CDR3sequence as set out in SEQ ID NO: 13; or comprising a heavy chainvariable region CDR1 sequence as set out in SEQ ID NO: 14, a heavy chainvariable region CDR2 sequence as set out in SEQ ID NO: 15 and a heavychain variable region CDR3 sequence as set out in SEQ ID NO: 56.

In accordance with the present invention, any of the above 14combinations of CDR1, CDR2 and CDR3 sequences exists in a humanmonoclonal antibody or functional fragment thereof further comprising inits light chain variable region a CDR1 comprising the amino acidsequence set out in SEQ ID NO: 16, a CDR2 comprising the amino acidsequence set out in SEQ ID NO: 17, and a CDR3 comprising the amino acidsequence set out in SEQ ID NO: 18.

Analgesic compositions or medicaments according to the inventioncomprising the above antibodies or functional fragments or uses thereofare embodiments of the invention.

In accordance with the present invention, the human monoclonal antibodyof the invention or functional fragment thereof comprises in its lightchain variable region an amino acid sequence as set out in SEQ ID NO:19. Preferred is a human monoclonal antibody or functional fragmentthereof, the light chain variable region comprising an amino acidsequence as set out in SEQ ID NO: 19 and a heavy chain variable regioncomprising an amino acid sequence as set out in SEQ ID NO: 20; or ahuman monoclonal antibody or functional fragment thereof, the lightchain variable region comprising an amino acid sequence as set out inSEQ ID NO: 19 and a heavy chain variable region comprising an amino acidsequence as set out in SEQ ID NO: 21; or a human monoclonal antibody orfunctional fragment thereof, the light chain variable region comprisingan amino acid sequence as set out in SEQ ID NO: 19 and a heavy chainvariable region comprising an amino acid sequence as set out in SEQ IDNO: 22; or a human monoclonal antibody or functional fragment thereof,the light chain variable region comprising an amino acid sequence as setout in SEQ ID NO: 19 and a heavy chain variable region comprising anamino acid sequence as set out in SEQ ID NO: 23; or a human monoclonalantibody or functional fragment thereof, the light chain variable regioncomprising an amino acid sequence as set out in SEQ ID NO: 19 and aheavy chain variable region comprising an amino acid sequence as set outin SEQ ID NO: 24; or a human monoclonal antibody or functional fragmentthereof, the light chain variable region comprising an amino acidsequence as set out in SEQ ID NO: 19 and a heavy chain variable regioncomprising an amino acid sequence as set out in SEQ ID NO: 25; or ahuman monoclonal antibody or functional fragment thereof, the lightchain variable region comprising an amino acid sequence as set out inSEQ ID NO: 19 and a heavy chain variable region comprising an amino acidsequence as set out in SEQ ID NO: 26; or a human monoclonal antibody orfunctional fragment thereof, the light chain variable region comprisingan amino acid sequence as set out in SEQ ID NO: 19 and a heavy chainvariable region comprising an amino acid sequence as set out in SEQ IDNO: 27; or a human monoclonal antibody or functional fragment thereof,the light chain variable region comprising an amino acid sequence as setout in SEQ ID NO: 19 and a heavy chain variable region comprising anamino acid sequence as set out in SEQ ID NO: 28; or a human monoclonalantibody or functional fragment thereof, the light chain variable regioncomprising an amino acid sequence as set out in SEQ ID NO: 19 and aheavy chain variable region comprising an amino acid sequence as set outin SEQ ID NO: 29; or a human monoclonal antibody or functional fragmentthereof, the light chain variable region comprising an amino acidsequence as set out in SEQ ID NO: 19 and a heavy chain variable regioncomprising an amino acid sequence as set out in SEQ ID NO: 30; or ahuman monoclonal antibody or functional fragment thereof, the lightchain variable region comprising an amino acid sequence as set out inSEQ ID NO: 19 and a heavy chain variable region comprising an amino acidsequence as set out in SEQ ID NO: 31; or a human monoclonal antibody orfunctional fragment thereof, the light chain variable region comprisingan amino acid sequence as set out in SEQ ID NO: 19 and a heavy chainvariable region comprising an amino acid sequence as set out in SEQ IDNO: 32; or a human monoclonal antibody or functional fragment thereof,the light chain variable region comprising an amino acid sequence as setout in SEQ ID NO: 19 and a heavy chain variable region comprising anamino acid sequence as set out in SEQ ID NO: 33; or a human monoclonalantibody or functional fragment thereof, the light chain variable regioncomprising an amino acid sequence as set out in SEQ ID NO: 19 and aheavy chain variable region comprising an amino acid sequence as set outin SEQ ID NO: 52; or a human monoclonal antibody or functional fragmentthereof, the light chain variable region comprising an amino acidsequence as set out in SEQ ID NO: 19 and a heavy chain variable regioncomprising an amino acid sequence as set out in SEQ ID NO: 53.

In accordance with the present invention, the human monoclonal antibodyof the invention or functional fragment thereof comprises in its lightchain variable region an amino acid sequence as set out in SEQ ID NO:54. Preferred is a human monoclonal antibody or functional fragmentthereof, the light chain variable region comprising an amino acidsequence as set out in SEQ ID NO: 54 and a heavy chain variable regioncomprising an amino acid sequence as set out in SEQ ID NO: 20; or ahuman monoclonal antibody or functional fragment thereof, the lightchain variable region comprising an amino acid sequence as set out inSEQ ID NO: 54 and a heavy chain variable region comprising an amino acidsequence as set out in SEQ ID NO: 21; or a human monoclonal antibody orfunctional fragment thereof, the light chain variable region comprisingan amino acid sequence as set out in SEQ ID NO: 54 and a heavy chainvariable region comprising an amino acid sequence as set out in SEQ IDNO: 22; or a human monoclonal antibody or functional fragment thereof,the light chain variable region comprising an amino acid sequence as setout in SEQ ID NO: 54 and a heavy chain variable region comprising anamino acid sequence as set out in SEQ ID NO: 23; or a human monoclonalantibody or functional fragment thereof, the light chain variable regioncomprising an amino acid sequence as set out in SEQ ID NO: 54 and aheavy chain variable region comprising an amino acid sequence as set outin SEQ ID NO: 24; or a human monoclonal antibody or functional fragmentthereof, the light chain variable region comprising an amino acidsequence as set out in SEQ ID NO: 54 and a heavy chain variable regioncomprising an amino acid sequence as set out in SEQ ID NO: 25; or ahuman monoclonal antibody or functional fragment thereof, the lightchain variable region comprising an amino acid sequence as set out inSEQ ID NO: 54 and a heavy chain variable region comprising an amino acidsequence as set out in SEQ ID NO: 26; or a human monoclonal antibody orfunctional fragment thereof, the light chain variable region comprisingan amino acid sequence as set out in SEQ ID NO: 54 and a heavy chainvariable region comprising an amino acid sequence as set out in SEQ IDNO: 27; or a human monoclonal antibody or functional fragment thereof,the light chain variable region comprising an amino acid sequence as setout in SEQ ID NO: 54 and a heavy chain variable region comprising anamino acid sequence as set out in SEQ ID NO: 28; or a human monoclonalantibody or functional fragment thereof, the light chain variable regioncomprising an amino acid sequence as set out in SEQ ID NO: 54 and aheavy chain variable region comprising an amino acid sequence as set outin SEQ ID NO: 29; or a human monoclonal antibody or functional fragmentthereof, the light chain variable region comprising an amino acidsequence as set out in SEQ ID NO: 54 and a heavy chain variable regioncomprising an amino acid sequence as set out in SEQ ID NO: 30; or ahuman monoclonal antibody or functional fragment thereof, the lightchain variable region comprising an amino acid sequence as set out inSEQ ID NO: 54 and a heavy chain variable region comprising an amino acidsequence as set out in SEQ ID NO: 31; or a human monoclonal antibody orfunctional fragment thereof, the light chain variable region comprisingan amino acid sequence as set out in SEQ ID NO: 54 and a heavy chainvariable region comprising an amino acid sequence as set out in SEQ IDNO: 32; or a human monoclonal antibody or functional fragment thereof,the light chain variable region comprising an amino acid sequence as setout in SEQ ID NO: 54 and a heavy chain variable region comprising anamino acid sequence as set out in SEQ ID NO: 33; or a human monoclonalantibody or functional fragment thereof, the light chain variable regioncomprising an amino acid sequence as set out in SEQ ID NO: 54 and aheavy chain variable region comprising an amino acid sequence as set outin SEQ ID NO: 52; or a human monoclonal antibody or functional fragmentthereof, the light chain variable region comprising an amino acidsequence as set out in SEQ ID NO: 54 and a heavy chain variable regioncomprising an amino acid sequence as set out in SEQ ID NO: 53.

In accordance with the present invention, the human monoclonal antibodyof the invention or functional fragment thereof comprises in its lightchain variable region an amino acid sequence as set out in SEQ ID NO:55. Preferred is a human monoclonal antibody or functional fragmentthereof, the light chain variable region comprising an amino acidsequence as set out in SEQ ID NO: 55 and a heavy chain variable regioncomprising an amino acid sequence as set out in SEQ ID NO: 20; or ahuman monoclonal antibody or functional fragment thereof, the lightchain variable region comprising an amino acid sequence as set out inSEQ ID NO: 55 and a heavy chain variable region comprising an amino acidsequence as set out in SEQ ID NO: 21; or a human monoclonal antibody orfunctional fragment thereof, the light chain variable region comprisingan amino acid sequence as set out in SEQ ID NO: 55 and a heavy chainvariable region comprising an amino acid sequence as set out in SEQ IDNO: 22; or a human monoclonal antibody or functional fragment thereof,the light chain variable region comprising an amino acid sequence as setout in SEQ ID NO: 55 and a heavy chain variable region comprising anamino acid sequence as set out in SEQ ID NO: 23; or a human monoclonalantibody or functional fragment thereof, the light chain variable regioncomprising an amino acid sequence as set out in SEQ ID NO: 55 and aheavy chain variable region comprising an amino acid sequence as set outin SEQ ID NO: 24; or a human monoclonal antibody or functional fragmentthereof, the light chain variable region comprising an amino acidsequence as set out in SEQ ID NO: 55 and a heavy chain variable regioncomprising an amino acid sequence as set out in SEQ ID NO: 25; or ahuman monoclonal antibody or functional fragment thereof, the lightchain variable region comprising an amino acid sequence as set out inSEQ ID NO: 55 and a heavy chain variable region comprising an amino acidsequence as set out in SEQ ID NO: 26; or a human monoclonal antibody orfunctional fragment thereof, the light chain variable region comprisingan amino acid sequence as set out in SEQ ID NO: 55 and a heavy chainvariable region comprising an amino acid sequence as set out in SEQ IDNO: 27; or a human monoclonal antibody or functional fragment thereof,the light chain variable region comprising an amino acid sequence as setout in SEQ ID NO: 55 and a heavy chain variable region comprising anamino acid sequence as set out in SEQ ID NO: 28; or a human monoclonalantibody or functional fragment thereof, the light chain variable regioncomprising an amino acid sequence as set out in SEQ ID NO: 55 and aheavy chain variable region comprising an amino acid sequence as set outin SEQ ID NO: 29; or a human monoclonal antibody or functional fragmentthereof, the light chain variable region comprising an amino acidsequence as set out in SEQ ID NO: 55 and a heavy chain variable regioncomprising an amino acid sequence as set out in SEQ ID NO: 30; or ahuman monoclonal antibody or functional fragment thereof, the lightchain variable region comprising an amino acid sequence as set out inSEQ ID NO: 55 and a heavy chain variable region comprising an amino acidsequence as set out in SEQ ID NO: 31; or a human monoclonal antibody orfunctional fragment thereof, the light chain variable region comprisingan amino acid sequence as set out in SEQ ID NO: 55 and a heavy chainvariable region comprising an amino acid sequence as set out in SEQ IDNO: 32; or a human monoclonal antibody or functional fragment thereof,the light chain variable region comprising an amino acid sequence as setout in SEQ ID NO: 55 and a heavy chain variable region comprising anamino acid sequence as set out in SEQ ID NO: 33; or a human monoclonalantibody or functional fragment thereof, the light chain variable regioncomprising an amino acid sequence as set out in SEQ ID NO: 55 and aheavy chain variable region comprising an amino acid sequence as set outin SEQ ID NO: 52; or a human monoclonal antibody or functional fragmentthereof, the light chain variable region comprising an amino acidsequence as set out in SEQ ID NO: 55 and a heavy chain variable regioncomprising an amino acid sequence as set out in SEQ ID NO: 53.

In accordance with the present invention, a human monoclonal antibody orfunctional fragment thereof is used, said antibody comprising in itslight chain a variable region a CDR1 region comprising an amino acidsequence as set out in SEQ ID NO: 16, a CDR2 region having an amino acidsequence as set out in SEQ ID NO: 17 and a CDR3 having an amino acidsequence as set out in SEQ ID NO: 18 and comprising in its heavy chainvariable region a CDR1 region comprising an amino acid sequence as setout in SEQ ID NO: 14, a CDR2 region having an amino acid sequence as setout in SEQ ID NO: 15 and a CDR3 having an amino acid sequence as set outin any of SEQ ID NOs. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 56,e.g., the heavy chain variable region comprises a CDR3 having an aminoacid sequence set out in SEQ ID No. 2.

Analgesic compositions or medicaments according to the invention or kitscomprising the above antibodies or functional fragments or uses thereofare embodiments of the invention.

In accordance with the present invention, the human monoclonal antibodycomprises in its light chain an amino acid sequence as set out in SEQ IDNO: 34 and in its heavy chain an amino acid sequence as set out in SEQID NO: 35; or in its light chain an amino acid sequence as set out inSEQ ID NO: 34 and in its heavy chain an amino acid sequence as set outin SEQ ID NO: 36; or in its light chain an amino acid sequence as setout in SEQ ID NO: 34 and in its heavy chain an amino acid sequence asset out in SEQ ID NO: 37; or in its light chain an amino acid sequenceas set out in SEQ ID NO: 34 and in its heavy chain an amino acidsequence as set out in SEQ ID NO: 38; or in its light chain an aminoacid sequence as set out in SEQ ID NO: 34 and in its heavy chain anamino acid sequence as set out in SEQ ID NO: 39; or in its light chainan amino acid sequence as set out in SEQ ID NO: 34 and in its heavychain an amino acid sequence as set out in SEQ ID NO: 40; or in itslight chain an amino acid sequence as set out in SEQ ID NO: 34 and inits heavy chain an amino acid sequence as set out in SEQ ID NO: 41; orin its light chain an amino acid sequence as set out in SEQ ID NO: 34and in its heavy chain an amino acid sequence as set out in SEQ ID NO:42; or in its light chain an amino acid sequence as set out in SEQ IDNO: 34 and in its heavy chain an amino acid sequence as set out in SEQID NO: 43; or in its light chain an amino acid sequence as set out inSEQ ID NO: 34 and in its heavy chain an amino acid sequence as set outin SEQ ID NO: 44; or in its light chain an amino acid sequence as setout in SEQ ID NO: 34 and in its heavy chain an amino acid sequence asset out in SEQ ID NO: 45; or in its light chain an amino acid sequenceas set out in SEQ ID NO: 34 and in its heavy chain an amino acidsequence as set out in SEQ ID NO: 46; or in its light chain an aminoacid sequence as set out in SEQ ID NO: 34 and in its heavy chain anamino acid sequence as set out in SEQ ID NO: 47; or in its light chainan amino acid sequence as set out in SEQ ID NO: 34 and in its heavychain an amino acid sequence as set out in SEQ ID NO: 48. Neutralizingantibodies comprising in the light chain an amino acid sequence as setout in SEQ ID NO: 34 and in its heavy chain an amino acid sequence asset out in SEQ ID NO: 35, or functional fragments of such antibodies,are embodiments of the invention.

Analgesic compositions or medicaments comprising the above antibodies orfunctional fragments or uses thereof are embodiments of the invention.

In accordance with the present invention, human monoclonal antibodymolecules and/or functional fragments thereof are provided which areespecially advantageous as neutralizers of the activity of primate,especially of human GM-CSF. Human monoclonal antibodies or functionalfragments thereof are highly advantageous for several reasons.

First, they recognize primate GM-CSF highly specifically, that is to saythat from a mixture of primate GM-CSF with other primate colonystimulating factors (for example primate G-CSF and M-CSF), the bindingmolecules according to these especially preferred embodiments are highlydiscriminating for primate GM-CSF, whereas the other colony stimulatingfactors in the same milieu are not recognized. This means that a humanmonoclonal antibody or functional fragment thereof according to theseembodiments, when administered to a human, will be expected tospecifically bind to and neutralize only the desired target, whereasother undesired targets are neither bound nor neutralized. Ultimately,this leads to a high degree of predictability concerning the therapeuticmode of action in vivo.

Second, binders according to these especially preferred embodiments bindto primate GM-CSF with extremely high affinity. K_(D) values of fromabout 4×10⁻⁹ M down to as low as about 0.04×10⁻⁹ M, the lattercorresponding to about 40 pM, have been observed for molecules of thisclass. Since the kinetic on-rate of such molecules in aqueous media islargely diffusion controlled and therefore cannot be improved beyondwhat the local diffusion conditions will allow under physiologicalconditions, the low K_(D) arises primarily as a result of the kineticoff-rate, k_(off), which for the highest affinity antibody binder isapproximately 10^(−5 −s). This means that once the complex between ahuman monoclonal antibody or functional fragment thereof according toany of these embodiments of the invention on the one hand and primateGM-CSF on the other hand is formed, it does not readily, or at leastdoes not quickly separate. For binding molecules intended asneutralizers of biological activity, these characteristics are highlyadvantageous since the desirable neutralizing effect will normally lastonly as long as the molecule, the biological activity of which is to beneutralized (here primate GM-CSF) remains bound by the neutralizingbinding molecule. So a neutralizing molecule which remains bound to itsintended target for a long time will continue to neutralize for acorrespondingly long time.

The high binding affinity of human monoclonal antibodies or functionalfragments thereof to primate GM-CSF has an additional advantage.Normally, antibodies or functional fragments thereof will be eliminatedfrom the bloodstream of a patient in a size-dependent fashion, withsmaller molecules being excreted and eliminated before larger ones.Since the complex of the two polypeptides—antibody or antibodyfunctional fragment and bound GM-CSF—is obviously larger than theantibody alone, the low k_(off) mentioned above has the effect thattherapeutic neutralizer is excreted and eliminated from the patient'sbody more slowly than would be the case, were it not bound to GM-CSF.Thus, not only the magnitude of the neutralizing activity but also itsduration in vivo is increased.

Accordingly, when the antibodies or functional fragments are used inmethods according to the invention or to provide analgesic medicamentsor analgesic pharmaceutical compositions, the duration of pain reductioncan be extended compared with less specific analgesics. An advantage ofthe antibodies or functional fragments or compositions and medicamentsof the present invention is that the period between two administrationsof the herein described medicaments, compositions or the activeingredients can be extended. Alternatively, the amount of activeingredients in compositions comprising the same as analgesic compound,due to its high affinity to GM-CSF, may be shortened compared with otheranalgesics that are less specific. This property of the compositions,medicaments, etc. of the present invention increases patient compliance.

Finally, the neutralizing activity determined for binders according tothese especially preferred embodiments is surprisingly high. As will bedescribed in more detail herein below, neutralizing activity wasmeasured in vitro using a TF-1 growth inhibition assay (Kitamura, T. etal. (1989). J Cell Physiol 140, 323-34). As an indication ofneutralizing potential, IC₅₀ values were measured, IC₅₀ representing theconcentration of human monoclonal antibody or functional fragmentthereof according to any of these embodiments of the invention requiredto elicit a half-maximal inhibition of TF-1 cell proliferation. Forhuman monoclonal antibodies or functional fragments thereof according toany of these embodiments of the invention an IC₅₀ value of approximately3×10⁻¹⁰ M, or about 0.3 nM was determined. The binding moleculesaccording to any of these embodiments of the invention are thereforehighly potent neutralizes of the activity of primate GM-CSF.

In summary, then, a human monoclonal antibody or functional fragmentthereof according to any of the above embodiments of the inventionexhibits high degree of discrimination for the desired antigen, bindsthis antigen extremely tightly and for a long time and exhibits highlypotent neutralizing activity for the long time it remains bound. At thesame time, the long persistence of the binder-antigen complex slowselimination of this binder from the body, thereby lengthening theduration of the desired therapeutic effect in vivo, and therebyadvantageously extending the time interval between two administrationsof compositions or medicaments according to the invention comprising theactive ingredients in the treatment of pain.

A further aspect of the invention provides a human monoclonal antibodyor functional fragment thereof comprising an amino acid sequence havingat least 70%, at least 75% at least 80% at least 85% at least 90% atleast 95%, e.g., at least 97% homology with an amino acid as set out inany of SEQ ID NOs: 1-48 and/or 52-56. Homology may be determined bystandard sequence alignment programs such as Vector NTI (InforMax™,Maryland, USA). Such programs compare aligned sequences on an aminoacid-by-amino acid basis, and can be set to various levels of stringencyfor the comparison (e.g. identical amino acid, conservative amino acidsubstitution, etc.). As the term is used herein, two amino acids inquestion are considered as being “conservative substitutions” of oneanother if they each belong to the same chemical class, i.e. acidic,nonpolar, uncharged polar and basic. By way of non-limiting example, twodifferent amino acids belonging to the class of nonpolar amino acidswould be considered “conservative substitutions” of one another, even ifthese two amino acids were not identical, whereas a nonpolar amino acidon the one hand and a basic amino acid on the other hand would not beconsidered “conservative substitutions” of one another. Panel 3.1 of“Molecular Biology of the Cell”, 4^(th) Edition (2002), by Alberts,Johnson, Lewis, Raff, Roberts and Walter groups amino acids into fourmain groups: acidic, nonpolar, uncharged polar and basic. Such agrouping may be used for the purposes of determining, for the purposesof the present invention, whether or not a particular amino acid is aconservative substitution of another amino acid in question.

A further aspect of the invention provides a polynucleotide moleculehaving a nucleotide sequence encoding an amino acid sequence as set outin any of SEQ ID NOs: 1-48 and/or 52 to 56 or a nucleotide sequenceexhibiting at least 70%, at least 75% at least 80% at least 85% at least90% at least 95%, e.g., at least 97% homology therewith, whereinhomology may be determined by comparing a nucleotide sequence encodingan amino acid sequence of any of SEQ ID NOS: 1-48 and/or 52-56 with anucleotide sequence in question by sequence alignment (as describedabove for amino acid sequences), wherein a nucleotide in the sequence inquestion is considered homologous if it is either identical to thecorresponding nucleotide in the nucleotide sequence encoding acorresponding amino acid sequence of any of SEQ ID NOs: 1-48 and/or52-56 or if one or more nucleotide deviation(s) in the sequence inquestion from the corresponding one or more nucleotide(s) in thenucleotide sequence encoding an amino acid sequence of any of SEQ IDNOs: 1-48 and/or 52-56 results in a nucleotide triplet which, whentranslated, results in an amino acid which is either identical to (dueto a degenerate triplet) or a conservative substitution of thecorresponding amino acid in the corresponding amino acid sequence of anyof SEQ ID NOs: 1-48 and/or 52-56. Here, the term “conservativesubstitution” is to be understood as described above.

A further aspect of the invention provides a pharmaceutical compositioncomprising a human monoclonal antibody or functional fragment thereof ora polynucleotide molecule having a nucleotide sequence encoding an aminoacid sequence as set out in any of SEQ ID NOs: 1-48 and/or 52-56 orencoding an amino acid sequence comprising an amino acid sequencebearing at least 70%, at least 75% at least 80% at least 85% at least90% at least 95%, e.g., at least 97% homology to any of SEQ ID NOs: 1-48and/or 52-56, wherein “homology” is to be understood as explainedhereinabove. In accordance with this invention, the term “pharmaceuticalcomposition” relates to a composition for administration to a patient,e.g., a human patient. In a preferred embodiment, the pharmaceuticalcomposition comprises a composition for parenteral, transdermal,subcutaneous, intraluminal, intra-arterial, intrathecal and/orintranasal administration or by direct injection into tissue. It is inparticular envisaged that said pharmaceutical composition isadministered to a patient via infusion or injection. Administration ofthe suitable compositions may be effected by different ways, e.g., byintravenous, intraperitoneal, subcutaneous, intramuscular, topical orintradermal administration. In preferred embodiments of the presentinvention, the analgesic compositions are suitable for subcutaneousadministration. Methods of treatment of subjects, e.g., human subjectsaccording to the present invention involve the subcutaneousadministration of analgesic compositions as described throughout thepresent disclosure. These methods comprise the administration of theinventive compositions to patients suffering from pain, e.g.pain-associated with RA. The pharmaceutical composition of the presentinvention may further comprise a pharmaceutically acceptable carrier.Examples of suitable pharmaceutical carriers are well known in the artand include phosphate buffered saline solutions, water, emulsions, suchas oil/water emulsions, various types of wetting agents, sterilesolutions, liposomes, etc. Compositions comprising such carriers can beformulated by well known conventional methods. These pharmaceuticalcompositions can be administered to the subject at a suitable dose. Thedosage regimen will be determined by the attending physician andclinical factors. As is well known in the medical arts, dosages for anyone patient depend upon many factors, including the patient's size, bodysurface area, age, the particular compound to be administered, sex, timeand route of administration, general health, and other drugs beingadministered concurrently. Preparations for parenteral administrationinclude sterile aqueous or non-aqueous solutions, suspensions, andemulsions. Examples of non-aqueous solvents are propylene glycol,polyethylene glycol, vegetable oils such as olive oil, and injectableorganic esters such as ethyl oleate. Aqueous carriers include water,alcoholic/aqueous solutions, emulsions or suspensions, including salineand buffered media. Parenteral vehicles include sodium chloridesolution, Ringer's dextrose, dextrose and sodium chloride, lactatedRinger's, or fixed oils. Intravenous vehicles include fluid and nutrientreplenishers, electrolyte replenishers (such as those based on Ringer'sdextrose), and the like. Preservatives and other additives may also bepresent such as, for example, antimicrobials, anti-oxidants, chelatingagents, inert gases and the like. In addition, the pharmaceuticalcomposition of the present invention might comprise proteinaceouscarriers, like, e.g., serum albumin or immunoglobulin, e.g., of humanorigin. It is envisaged that the pharmaceutical composition of theinvention might comprise, in addition to the human monoclonal antibodyor functional fragment thereof (as described in this invention), furtherbiologically active agents, depending on the intended use of thepharmaceutical composition. Such agents might be drugs acting on thegastrointestinal system, drugs acting as cytostatica, drugs preventinghyperurikemia, drugs inhibiting immunoreactions (e.g. corticosteroids),drugs modulating the inflammatory response, drugs acting on thecirculatory system and/or agents such as cytokines or other analgesics,e.g. NSAIDs, COX-2 inhibitors, tramadol hydrochloride, known in the art,antibiotic and antimicrobial drugs, anticoagulation drugs, cholesterolreducing drugs, statins, anti-depressive drugs, antihypertensive drugs,nitroglycerin, and other heart medication drugs. The dosage of suchadditional compounds will also be determined by the attending physicianand clinical factors, e.g. the patient's size, body surface area, age,the particular compound to be administered, sex, time and route ofadministration, general health, and other drugs being administeredconcurrently.

It is of particular importance that the neutralizing antibodies and/orfunctional fragments thereof provide a sufficient stability uponstorage. It is possible to produce a wide variety of proteins fortherapeutic applications. After their production, proteinpharmaceuticals are usually stored prior to their use. Due to the factthat proteins are generally larger and more complex than “traditional”pharmaceuticals, formulation and processing of protein pharmaceuticalsthat are suitable for storage can be particularly challenging. Forreviews of protein pharmaceutical formulation and process design, seeCarpenter et al. (1997), Pharm. Res. 14: 969-975; Wang (2000), Int. J.Pharmaceutics 203: 1-60; and Tang and Pikal (2004), Pharm. Res. 21:191-200. Several factors can be considered in designing formulations andprocesses for protein pharmaceutical production. Of primary concern isthe stability of the protein through any or all steps of manufacture,shipping, and handling steps, which may include preparation of thecomposition, freezing, lyophilizing, drying, storage, shipping,reconstitution, freeze/thaw cycles, and post-reconstitution storage bythe end user. Other potential considerations include ease and economy ofmanufacture, handling, and distribution; composition of the finalproduct for patient administration; and ease of use by the end user,including solubility of the lyophilized formulation upon reconstitution.

Stable formulation comprising the neutralizing anti-GM-CSF antibody orfunctional fragments thereof according to the present invention can beregarded as an aqueous solution, wherein the antibody or functionalfragments thereof are directly dissolved and/or dispersed therein. Anembodiment of the present invention is a liquid formulation containingthe antibody or functional fragments thereof which is stable and doesnot undergo the formation of conjugates/aggregates or functionalfragments/degradation products when stored for a long period, and whichformulation is suitable for subcutaneous administration.

Specifically, the neutralizing anti-GM-CSF antibody or functionalfragments thereof could be stabilized if a tonicity modifier is added tothe solution which is to be stored. Examples for tonicity modifiersinclude, but are not limited to, sugars and sugar alcohols. Simplesugars are called monosaccharides and include glucose, fructose,galactose, xylose, ribose, mannose, lactulose, allose, altrose, gulose,idose, talose, arabinose and lyxose. More preferred for the presentinventions are disaccharides which include for example sucrose, maltose,lactose, isomaltose, trehalose and cellubiose. Sugar alcohols includesorbitol, mannitol, glycerin, erythritol, maltitol, xylitol,polyglycitol. In a preferred embodiment, the sugar is a non-reducingsugar such as sucrose or trehalose. Non-reducing sugars arecharacterized by the absence of an open chain structure, so they are notsusceptible to oxidation-reduction reactions. Therefore one or more ofnon-reducing sugars, such as sucrose or trehalose, or one or more ofsugar alcohols, such as mannitol or sorbitol could be added to theformulation comprising a compound neutralizing GM-CSF. Also combinationsof non-reducing sugars and sugar alcohols could be added to thesolution, such as sucrose and mannitol, sucrose and sorbitol, trehaloseand mannitol, or trehalose and sorbitol. More preferably the sugaralcohols mannitol and/or sorbitol are added, e.g., in their D-form, mostpreferably sorbitol is added to the solution. The concentration of thetonicity modifier, e.g., sorbitol, is between about 1% and about 15%(w/v), e.g., between about 2% and about 10% (w/v), e.g., between about3% and about 7% (w/v), e.g., between about 4% and about 6% (w/v) andpreferably about 5% (w/v).

Another specifically preferred substance to stabilize the neutralizinganti-GM-CSF antibody or functional fragments thereof at a highconcentration with regard to long-term storage is a buffer system with apH of between about 4 and about 10, e.g., between about 4 and about 7,e.g., between about 4 and about 6 or between about 5 and about 7, e.g.,between about 5.5 and about 6.5, preferably with a pH of about 5.8. Thebuffer may be preferably selected from a histidine buffer, an acetatebuffer and a citrate buffer. When referred herein, an amino acid ismeant to be an L-amino acid or D-amino acid, wherein L-amino ispreferred. Preferably histidine or a salt thereof is used for the buffersystem. Preferably the salt is a chloride, phosphate, acetate orsulphate, more preferably the salt is a chloride. The pH of thehistidine buffer system is between about 5 and about 7, preferablybetween about 5.5 and about 6.5, more preferred the pH is about orexactly 5.8. The pH may be adjusted by the use of conventionally usedbases and acids, preferably NaOH. The concentration of the buffersystem, preferably the histidine buffer system, is between about 10 mMand about 50 mM, preferably between about 20 mM and about 40 mM, morepreferably about 30 mM.

According to a preferred embodiment, a combination of the buffer system,preferably the histidine buffer, and the tonicity modifier, preferablythe sugar alcohol, more preferably mannitol or even more preferablysorbitol, is used to stabilize the neutralizing anti-GM-CSF antibody orfunctional fragments thereof in the solution, in order to preventaggregation and to render the formulation sufficiently stable forlong-term storage and/or one or more freeze/thaw cycles. It was shownthat it is preferable in terms of stability to have about 6% (w/v) andhigher of sugar alcohol, preferably sorbitol, in the formulation.However, the upper limit for osmolality of the formulation is set to beabout 470 mOsm/kg which is still hyperosmotic. A preferableconcentration of sugar alcohol, preferably sorbitol, is thereforebetween about 3% and about 7% (w/v), more preferably between about 4%and about 6% (w/v) and most preferably about 5% (w/v). In someembodiments of the present invention, the formulations or compositionsof the invention comprising the neutralizing anti-GM-CSF antibody orfunctional fragments thereof do not require further excipients inaddition to those disclosed above (i.e., a buffer and a tonicitymodifier), such as, for example, surfactants and amino acids, which areused in traditional formulations to stabilize proteins in solution. Inaddition, the formulations described herein are preferred over standardformulations because they have decreased immunogenicity due to the lackof additional agents commonly needed for protein stabilization. It isknown that amino acids are useful to stabilize proteins at a highconcentration by, inter alia, mediating protein solubility and/orinhibiting protein aggregation. Although threonine (e.g. at 250 mM)indicates a minor stabilizing effect, the liquid formulation comprisingthe neutralizing anti-GM-CSF antibody or functional fragments thereof ispreferably free from further amino acids.

Furthermore, it is preferred that the present formulation is free oressentially free of sodium chloride. By “essentially free” is meant thatthe concentration of sodium chloride is at or very near to 0 (zero) mM,e.g. less than about 50 mM, preferably less than about 20 mM, morepreferably less than about 10 mM, even more preferably less than about 5mM and most preferably less than about 2 mM or even less than about 1mM.

In biopharmaceutical products, the addition of surfactants can be usefulto reduce protein degradation during storage. The polysorbates 20 and 80(Tween 20 and Tween 80) are well established excipients for thispurpose.

In a more preferred embodiment the polysorbate 20 to protein ratio isbetween about 0.01:1 to about 3:1, preferably between about 0.05:1 toabout 2:1, more preferably between about 0.1:1 and about 1.5:1, evenmore preferably between about 0.1:1 to about 0.8:1, and most preferablybetween about 0.1:1 to about 0.2:1. For a protein concentration of 80mg/mL, the polysorbate 20 concentration is between about 0.001% (w/v)and about 0.2% (w/v), preferably between about 0.005% (w/v) and about0.15% (w/v), more preferably between about 0.007% (w/v) and about 0.1%(w/v), even more preferably between about 0.007% (w/v) and about 0.06%(w/v) and most preferably about 0.01% (w/v). For a protein concentrationof 150 mg/mL, the polysorbate 20 concentration is between about 0.001%(w/v) and about 0.4% (w/v), preferably between about 0.006% (w/v) andabout 0.25% (w/v), more preferably between about 0.01% (w/v) and about0.18% (w/v), even more preferably between about 0.01% (w/v) and about0.1% (w/v) and most preferably about 0.02% (w/v).

In another more preferred embodiment, the polysorbate 80 to proteinratio is between about 0.01:1 to about 3:1, preferably between about0.05:1 to about 2:1, more preferably between about 0.1:1 and about1.5:1, even more preferably between about 0.1:1 to about 0.6:1, and mostpreferably from about 0.3:1 to about 0.6:1. For a protein concentrationof 80 mg/mL, the polysorbate 80 concentration is between about 0.001%(w/v) and about 0.2% (w/v), preferably between about 0.004% (w/v) andabout 0.14% (w/v), more preferably between about 0.007% (w/v) and about0.1% (w/v), even more preferably between about 0.007% (w/v) and about0.05% (w/v), and most preferably about 0.04% (w/v). For a proteinconcentration of 150 mg/mL, the polysorbate 80 concentration is betweenabout 0.001% (w/v) and about 0.4% (w/v), preferably between about 0.007%(w/v) and about 0.26% (w/v), more preferably between about 0.01% (w/v)and about 0.2% (w/v), even more preferably between about 0.01% (w/v) andabout 0.08% (w/v), most preferably about 0.04% (w/v).

The concentration of the neutralizing anti-GM-CSF antibody or functionalfragments thereof used is at least about 20 mg/ml, preferably at leastabout 50 mg/ml, more preferably at least about 100 mg/ml in the liquidformulation which is to be stored, freeze/thawed and/or ready to use.Concentrations of about 20 mg/ml to about 200 mg/mg, preferably about 50mg/ml to about 200 mg/ml, more preferably about 100 mg/ml to about 180mg/ml, even more preferably about 130 mg/ml to about 170 mg/ml, evenmore preferably about 135 mg/ml to about 165 mg/ml, and most preferredabout 150 mg/ml are used in the present invention. Another preferredconcentration of the neutralizing anti-GM-CSF antibody or functionalfragments thereof used is about 80 mg/ml.

Furthermore, in one embodiment, the present formulation of theneutralizing anti-GM-CSF antibody or functional fragments thereofcomprises from about 135 mg/ml to about 165 mg/ml of the neutralizingantibody, about 5% (w/v) sorbitol, about 30 mM L-histidine and has a pHof about 5.8.

Furthermore, in one embodiment, the present formulation of theneutralizing anti-GM-CSF antibody or functional fragments thereofcomprises from about 80 mg/ml to about 150 mg/ml of the neutralizingantibody, about 5% (w/v) sorbitol, about 30 mM L-histidine, and fromabout 0.01% to about 0.08% (w/v) polysorbate 80 and has a pH of about5.8.

Furthermore, in one embodiment, the present formulation of theneutralizing anti-GM-CSF antibody or functional fragments thereofcomprises about 80 mg/ml to of the neutralizing antibody, about 5% (w/v)sorbitol, about 30 mM L-histidine, about 0.04% (w/v) polysorbate 80 andhas a pH of about 5.8.

Furthermore, in one embodiment, the present formulation of theneutralizing anti-GM-CSF antibody or functional fragments thereofcomprises about 150 mg/ml to of the neutralizing antibody, about 5%(w/v) sorbitol, about 30 mM L-histidine, about 0.04% (w/v) polysorbate80 and has a pH of about 5.8.

The shelf life of the produced liquid formulation has a preferredminimum requirement of 24 months at 2 to 8° C., preferably 36 months at2 to 8° C., more preferably 48 months at 2 to 8° C. or at least 28 daysat ambient temperature (25° C.±2° C.).

The neutralizing anti-GM-CSF antibody or functional fragments thereof isprovided in a stable formulation, e.g., a stable liquid formulation thatsurprisingly allows for long-term storage of compounds neutralizingGM-CSF. This formulation is useful, in part, because it is moreconvenient to use for the patient, as the neutralizing anti-GM-CSFantibody or functional fragments thereof of this formulation are highlyconcentrated so as to reduce side effects like pain due to high volumeinjection.

Accordingly, the formulations comprising a neutralizing anti-GM-CSFantibody or functional fragments thereof according to the inventioncomprise a buffer system preferably selected from a histidine buffer, anacetate buffer and/or a citrate buffer with a preferred pH of between 5and 7, and a tonicity modifier preferably selected from non-reducingsugars, such as sucrose or trehalose, or sugar alcohols, such asmannitol or sorbitol are rendered sufficiently stable for long-termstorage and/or freeze/thaw cycles. The formulation of the invention hasmany advantages over standard buffered formulations. In one aspect, theformulation shows minimal aggregation behaviour upon long-term storagewithout deleterious effects that might be expected with high proteinformulations. Other advantages of the formulation according to theinvention are: minimal functional fragmentation of neutralizinganti-GM-CSF antibody or functional fragments thereof and no significantimpact on bioactivity of neutralizing anti-GM-CSF antibody or functionalfragments thereof over long-term storage, and low viscosity of thecomposition. Finally, in a preferred embodiment, the formulation is freeof further excipients such as surfactants, additional amino acids and/orsodium chloride.

A further aspect of the invention provides a use of a human monoclonalantibody or functional fragment thereof as described hereinabove or apolynucleotide molecule comprising a nucleotide sequence encoding anamino acid sequence as set out in any of SEQ ID NOs: 1-48 and/or 52-56or encoding an amino acid sequence comprising an amino acid sequencebearing at least 70% homology, at least 75% at least 80% at least 85% atleast 90% at least 95%, e.g., at least 97% to any of SEQ ID NOs: 1-48and/or 52-56, wherein “homology” is to be understood as explainedhereinabove, in the manufacture of a medicament for the treatment ofrheumatoid arthritis, SLE, psoriatic arthritis, ankylosing spondylitis,juvenile idiopathic arthritis, or osteoarthritis with concommitant pain,e.g., rheumatoid arthritis (RA), including RA which is insufficientlycontrolled by treatment with MTX and/or TNF inhibitors.

A further aspect of the invention provides a use of a human monoclonalantibody or functional fragment thereof as described hereinabove or apolynucleotide molecule comprising a nucleotide sequence encoding anamino acid sequence as set out in any of SEQ ID NOs: 1-48 and/or 52-56or encoding an amino acid sequence comprising an amino acid sequencebearing at least 70% homology, at least 75% at least 80% at least 85% atleast 90% at least 95%, e.g., at least 97% to any of SEQ ID NOs: 1-48and/or 52-56, wherein “homology” is to be understood as explainedhereinabove in the manufacture of a medicament, optionally comprisingone or more analgesics, e.g. NSAIDs, COX-2 inhibitors, anti-inflammatoryagents, e.g. methotrexate, etc. are especially preferred. Furthermore,the antibodies or functional fragments thereof or homologs thereof canbe used in the manufacture of a medicament further comprisingantagonists of the receptor for GM-CSF (GM-CSF-receptor), wherein theantagonists may be small molecules, small blocking peptides orantibodies neutralizing the activity of the GM-CSF-receptor, e.g.through prevention of the binding of natural ligand (GM-CSF) or anymolecules that induce downstream signaling events, e.g., downstreamsignaling in neurons expressing the GM-CSF-receptor. The prevention ofdownstream signaling may be determined by any suitable method for themeasurement of the activation of neurons, e.g. patch-clamp methodsmeasuring the ion-flux, or other methods known in the art. Additionally,the present methods and compositions may be used for the treatment ofarthritis associated with various syndromes, diseases, and conditions,such as arthritis associated with vasculitic syndrome, arthritisassociated with polyarteritis nodosa, arthritis associated withhypersensitivity vasculitis, arthritis associated with Luegenec'sgranulomatosis, arthritis associated with polymyalgin rheumatica, andarthritis associated with joint cell arteritis. Other preferredindications contemplated for employing the compositions and methodsherein include calcium crystal deposition arthropathies (such as pseudogout), non-articular rheumatism (such as bursitis, tenosynovitis,epicondylitis, carpal tunnel syndrome, and repetitive use injuries),neuropathic joint disease, hemarthrosis, Henoch-Schonlein Purpura,hypertrophic osteoarthropathy, and multicentric reticulohistiocytosis.Other preferred indications contemplated for employing the compositionsand methods herein include arthritic conditions associated withsarcoidosis, hemochromatosis, sickle cell disease and otherhemoglobinopathies, hyperlipoproteineimia, hypogammaglobulinemia,hyperparathyroidism, acromegaly, familial Mediterranean fever, Behcet'sDisease, lupus (including systemic lupus erythematosus), hemophilia,relapsing polychondritis, lumbago, and pain associated with herniateddisc.

The present disclosure relates to compositions, dosage forms, and kitswith a neutralizing antibody specifically binding to primate GM-CSF or afunctional fragment thereof in the treatment of pain optionally incombination with another analgesic, wherein the amount of said analgesicenhances the potency of the analgesic of the present invention, orwherein the amounts of the neutralizing antibody specifically binding toprimate GM-CSF or a functional fragment thereof and the amount of theother analgesic together are effective to alleviate (e.g., ameliorate,attenuate, reduce, diminish, block, inhibit or prevent) one or moresymptoms or signs of an arthritic condition, or chronic pain. Thedisclosure further relates to methods for administering to humansubjects such compositions, dosage forms, and kits.

The methods comprise administering to a human subject an amount of aneutralizing antibody specifically binding to primate GM-CSF or afunctional fragment thereof or the combination of said neutralizingantibody specifically binding to primate GM-CSF or a functional fragmentthereof, and another analgesic that is effective to enhance potency ofthe neutralizing antibody specifically binding to primate GM-CSF or afunctional fragment thereof and/or to alleviate one or more symptoms orsigns of an arthritic condition or pain associated with a chroniccondition, including for example, as measured by a suitable index, scaleor measure. The attenuation of one or more symptoms or signs of anarthritic may be measured on the WOMAC Osteoarthritis Index or one ofits subscales (in other words, the pain, stiffness, or physical functionsubscales of the WOMAC Osteoarthritis Index). Any suitable version ofthe WOMAC OA Index may be used, including, for example, Version 3.0 orVersion 3.1. Any suitable scale may be used as well. The WOMAC OA Indexis available in Likert and Visual Analog scaled formats, either of whichmay be employed in the present methods. WOMAC values can be consideredas surrogate markers for the diagnosis, prognosis, monitoring ortreatment of an arthritic condition, and/or chronic pain. The WOMACvalues represent a subjective surrogate marker. Alternatively oradditionally, the attenuation of one or more symptoms or signs may bemeasured on another suitable index, scale or measure, such theAustralian/Canadian (AUSCAN) Osteoarthritis Hand Index or theOsteoarthritis Global Index (OGI). The AUSCAN 3.1 Index and User Guideare currently available from http://www.womac.org/contact/index.cfm, asare the WOMAC 3.1 Osteoarthritis Index and User Guide. Another suitablemeasure of attenuation is the Definition of Improvement in RheumatoidArthritis described in Felson et al., Arthritis & Rheumatism 38:727-735(1995) incorporated herein by reference. This measure, which also may bedesignated as the ACR (American College of Rheumatology) 20 improvement,is a composite defined as both improvement of 20% in the number oftender and number of swollen joints, and a 20% improvement in three ofthe following five: patient global, physician global, patient pain,patient function assessment, and C-reactive protein (CRP). Anothersuitable measure is described by Paulus et al., Arthritis & Rheumatism33:477-484 (1990) which is incorporated herein by reference. Paulus etal. provides a definition of improvement based on a set of measures thatdiscriminate between active second-line drug treatment and placebo.These include a 20% improvement in morning stiffness, erythrocytesedimentation rate (ESR), joint tenderness score, and joint swellingscore and improvement by at least 2 grades on a 5-grade scale (or fromgrade 2 to grade 1) for patient and physician global assessments ofcurrent disease severity. Current disease severity can be measured in avariety of ways, including patient or physician global assessments,patient or physician assessments of joint tenderness, joint swellingstiffness, pain, or physical function, cytokine levels, B-cell or T-cellsubtype ratios, erythrocyte sedimentation rate (ESR), or C-reactiveprotein. Suitable measures of attenuation of one or more symptoms orsigns, of inhibiting the progression of an arthritic condition orchronic condition, or of reversing tissue or cellular damage includemeasuring current disease severity. Other indexes, definitions,measures, or scales may also be used for measuring attenuation of one ormore symptoms or signs, inhibition of progression, or reversal of tissueor cellular damage.

EXAMPLES Example 1

A phase 2 multicenter, randomized, double-blind, placebo-controlled,parallel group dose finding trial with different dose arms designed tocompare three different dose levels of an antibody neutralizing GM-CSF(hereinafter referred to as “anti-GM-CSF-1”) comprising a light chainCDR1 as depicted in SEQ ID NO: 16, a light chain CDR2 shown in SEQ IDNO: 17, a light chain CDR3 according to SEQ ID NO: 18, a heavy chainCDR1 shown in SEQ ID NO: 14, a heavy chain CDR2 shown in SEQ ID NO: 15,and a heavy chain CDR3 as depicted in SEQ ID NO: 2 (an antibody having avariable heavy chain and light chain as specified in SEQ ID Nos. 34 and35) is used at doses of 20 mg, 80 mg or 150 mg administeredsubcutaneously at week 0, 2, 6, 10, 14, 18, 22 in combination withstable continued dose of MTX versus placebo. Preparation of thisantibody is disclosed in WO 2006/111353.

The effect of anti-GM-CSF-1 on disease activity and signs and symptomswill be assessed by examination of joints (66 swollen and 68 tenderjoints) by a blinded assessor. Acute phase reactants e.g. DAS28CRP willbe measured in serum and ESR will be measured in blood at all visits.Effect on function (HAQ-DI) and Patient's and Physician's globalassessment of the disease activity will be assessed using a Visualanalogue scale (VAS) at all site visits.

Effect on RA pain intensity will be investigated using electroniccapturing of VAS pain measures from two weeks prior to baseline and willhave daily monitoring throughout the treatment period. Change in qualityof pain will be assessed by questionnaires at week 1, 12 and 24. SLANSSis assessed at baseline, week 2, 12 and 24. For VAS pain it is assessedat all visits up to week 24. Quality of life and patient reportedoutcomes will also be explored. Change in structural joint damage (mTSSchange from baseline) will be explored at week 24. The primary endpointat week 12 (DAS28-CRP mean change from baseline) is 2 weeks after the4th administration of anti-GM-CSF-1 or placebo.

Based on improvement in tender and swollen joint count at week 12 earlyescape to treatment of non-responders will be allowed from week 14.

The subject population will be subjects with moderate to severe RA for≥6 months disease duration and insufficiently controlled by either MTXalone or MTX in combination with one or more other DMARD(s) or one priorTNF inhibitor.

A total of 324 subjects will be randomly assigned to one of thetreatment groups for the treatment period in a 1:1:1:1 ratio. Thebaseline randomization will also cover the treatment in the activeextension period, in which subjects continue on the same dose, exceptfor subjects randomized to placebo who at week 24 will randomly beallocated to either 80 or 150 mg which will consequently be a 1:1 ratioof the (80, 150 mg) doses.

The study consists of the following periods:

-   -   Screening period (week −8/−2 to Baseline Visit).    -   Treatment period (Baseline Visit 3 (Day 1) to week 24).    -   Active extension period (week 24 to week 72).    -   Safety follow-up period (week 72 to week 80/12 weeks after last        administration).

Study Population

RA patients whose disease is not sufficiently controlled on MTX and/orother DMARDs in monotherapy or in combination or glucocorticoids (GC) ata dose of no more than 10 mg/day are eligible to have biologics added tocurrent MTX/DMARD/GC therapy according to current recommendations.

In the trial, anti-GM-CSF-1 will be tested as second line treatment inbiologic naïve patients, and as third line treatment in patients whohave failed treatment with anti-TNF compounds.

Patients in the trial must have had RA defined by the 1987 ACR criteriafor at least 6 months prior to trial entry. The bio-naïve patients musthave been treated with MTX for three months, and are thus eligible to asecond-line treatment. Patients had to have active disease defined asswollen and tender joint count ≥4 for each (referred to the 28joint-count system), and DAS28CRP and DAS28ESR > or equal 3.2, with 4 ormore swollen joints, which usually is found in RA patients with thisdisease activity. Furthermore the patients should be in current stabletherapy with MTX.

Selecting a population with this characteristics aims to ensure thatanti-GM-CSF-1 is tested in combination with the anchor drug MTX in anappropriate patient population eligible for biologic treatment and witha disease activity that gives a high probability of reducing signs andsymptoms of RA.

Study Design and Sample Size

The current design offers an above 90% power to detect a relevantdifference to placebo on the primary endpoint (DAS28CRP mean change frombaseline at week 12).

Concomitant Medications and Controls

The choice of controls is also in accordance with the CPMP/EMA Guideline(December 2003, 4). Section 5.1 of the guideline recommends use ofplacebo controls for a limited duration of 3 to 6 months. The use of MTXmonotherapy in the placebo arm is needed for the evaluation ofsuperiority of any dose level of anti-GM-CSF-1 plus MTX compared to MTXalone, but also to get an indication of the magnitude of the response ifit is found.

The chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) withgastric protection, low dose corticosteroids and hydroxychloroquine, allin stable doses, is allowed in the study to ensure adequate medicalcare.

Efficacy Endpoints

The continuous endpoint DAS28 (DAS28-CRP) was selected as primaryendpoint as it is considered a more sensitive endpoint for signs andsymptoms compared to the more traditional dichotomous ACR20 responserates and it is an absolute parameter used in daily clinical practice tofollow disease activity and has been confirmed to be a suitableparameter for the evaluation of disease activity in clinical trials withRA according to EULAR/ACR Collaborative Recommendations (Fransen and VanRiel 244; Aletaha et al. 1371-77).

To further evaluate the efficacy of anti-GM-CSF-1 in combination withMTX in reducing signs and symptoms of RA, the proportions of subjectsachieving ACR 20/50/70 and EULAR good and moderate response will beassessed at time of the primary endpoint or after 24 weeks. Theproportion of RA patients achieving remission as defined by DAS28-CRP,SDAI, CDAI and the new ACR/EULAR remission criteria will be assessed assecondary endpoints at week 12 and 24.

Disease modifying anti-rheumatic drugs (DMARDs) for treatment of RA haveto demonstrate ability to prevent or slow progression of structuraljoint damage. The effect of anti-GM-CSF-1 on inhibition of structuraljoint damage will therefore be explored after 24 weeks treatment in thisdose finding trial, as well as in an extension period up to week 72.X-rays will be assessed under blinded conditions.

Trial Duration

For the majority of biologics in RA, it will take up to 24 weeks togenerate a deep inflammation control measurable as DAS28 remission orhigh level ACR responses such as ACR50/70. Therefore, in this trial thedouble blind treatment period is 24 weeks.

Active Extension Period (Week 24 to 72)

Responders at week 24 will be eligible to continue on their currentdouble blind dose of anti-GM-CSF-1 until week 70 provided that thoroughevaluation of the safety across the dose level by the DMC has notrevealed any risk benefit issue that prevent an extension period.Subjects randomized at baseline to placebo and who are responders atweek 24 will be eligible to continue into the active extension periodrandomized to one of the highest dose levels anti-GM-CSF-1 (80 mg, 150mg) subcutaneously administered every 4 weeks for at least 12 weeks. Thejustification of this handling of placebo responders after 24 weeks isthat achieving a low disease activity or an improvement of DAS28CRP>1.2from baseline is not an ultimately achievable goal in RA, and an evenbetter clinical response can be pursued in these subjects. Given they doachieve a improved clinical response (change in DAS28-CRP>1.2) after 12weeks in the active extension period they should be eligible to continuefor the whole active extension period up to week 70 on this dose.

1.1 Screening Period

Subjects will be screened at the Screening Visit between week −8 andweek −3 before IMP administration, allowing for careful evaluation ofthe eligibility of the subjects and for the washout of TNF inhibitorand/or DMARDs except MTX (and hydroxycholoroquine and chloroquine),Three weeks prior to Baseline the subject will return to the site forvisit where the eligibility will be checked, and subjects will betrained in obtaining electronic capturing of VAS pain, VAS Fatigue andmorning stiffness daily from three weeks prior to baseline and untilweek 24.

Subjects will return to the clinic on Day 1, undergo baselineassessments and confirmation of eligibility and if eligible berandomized to one of the treatment groups in the treatment period aswell as the active extension period.

1.2 The Treatment Period

Eligible subjects will return to the clinic on Day 1 when eligibilitycriteria will be reviewed again, vital signs will be recorded, lungfunctions test will be performed, clinical efficacy assessment, bloodspecimens will be collected and the subject will have one subcutaneousinjection of anti-GM-CSF-1 or placebo.

Before leaving the site the subject will have a follow up evaluation anda blood specimen drawn for pharmacokinetic analysis.

In the treatment period (week 1 to 24) subjects will return to the studycenter for dosing at week 2 (w2), 6, 10, 14, 18, 22. Before dosing,vital signs, lung function test and an examination of the injection sitewill be undertaken. Clinical efficacy assessment (SJC and TJC) by atrained blinded assessor will be undertaken at all visits beforeanti-GM-CSF-1 administration. In addition a blood sample forpharmacokinetic and biomarker analysis will be drawn beforeanti-GM-CSF-1 administration.

Subjects will have disease activity and safety (including laboratoryevaluation) assessed two weeks after first anti-GM-CSF-1 administrationand subsequently every month. Nine site visits in the treatment periodare planned (visit 3 to visit 11).

X-ray of hands (posteroanterior view) and forefeet (anteroposteriorview) will be obtained and digitalised for blinded reading at baselineand at week 24 and for those subjects that participate in the activeextension period at week 72 or at last study visit. Assessment will bedone centrally by readers with no knowledge of the treatment allocationsand blinded to the order at which the images had been obtained, usingthe van der Heijde modification of Sharp method (mTSS).

1.3 Active Extension Period (Week 24 to 72)

Subjects who at week 24 have achieved low disease activity(DAS28CRP<3.2) or have a DAS28CRP reduction ≥1.2 from baseline to week24 will be eligible. Subjects will continue on the same dose as in thetreatment period and treatment will be kept blinded. However, patientstreated with placebo in the treatment period and who meet this responsecriteria will not continue on placebo, but will receive either 80 mg or150 mg anti-GM-CSF-1, 1:1, in the active extension period and beeligible to continue in the active extension period up to week 72 ifthey achieve a low disease activity DAS28CRP<3.2 or have a DAS28CRPreduction ≥1.2 after the initial 12 weeks in the active extensionperiod. If not they will have to leave the trial.

In the active extension period, disease activity and safety (includinglaboratory evaluation) will be assessed regularly the first 3 months andsubsequently every 3 months until week 72.

1.4 Safety Follow Up Period (12 Weeks after Trial Completion/PrematureDiscontinuation)

Two site contacts, where the first one can be a phone call, arescheduled to follow up on possible adverse events and immunogenicitybefore end of the trial. In this period, the investigator can at owndiscretion start treatment of the subject per current medical practice.

For subjects who enter into the active extension period, the trial willhave a total duration of up to 88 weeks.

Data on exposure of anti-GM-CSF-1 (PK) will be collected during thetreatment period at all dosing visits. Furthermore, PK data will becollected during the active extension period according to the scheduleof study procedures.

Example 2

A 24-week randomized, open-label, parallel-group, active-controlled,exploratory, proof-of-mechanism imaging study investigating the efficacyof 150 mg of neutralizing anti-primate GM-CSF referred to in Example 1administered subcutaneously compared with anti-TNF antibody Adalimumabin patients with moderate to severe early RA diagnosed within 6 monthsand inadequately controlled by MTX alone.

A total of 36 subjects will be enrolled and will remain in the study fora maximum of 44 weeks. The study consists of the following periods:

-   -   Screening Period (Week −4/−2 to Baseline Visit).    -   Treatment Period (Baseline Visit [Day 1] to Week 24).    -   Treatment-Free Period (Week 25 to Week 40).    -   End of Study Visit (Week 40).

Subjects will be randomly assigned in a 2:1 ratio to the followingopen-label treatment groups:

-   -   1) Neutralizing anti-primate GM-CSF 300 mg subcutaneous (SC) as        loading dose that is administered at Week 0 followed thereafter        by 150 mg SC administered at Weeks 2, 6, 10, 14, 18, and 22 as        an add-on to weekly existing stable MTX and folic acid: 24        subjects;    -   2) Active control, adalimumab 40 mg SC administered at Weeks 0,        2, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 22 as an add-on to        weekly existing stable MTX and folic acid: 12 subjects.

Primary Objective(s)

To explore the effect on structural damage imaging markers measured aschange from baseline in synovitis, erosion progression and bone marrowoedema (osteitis), in metocarpophalangeal (MCP) joints and wrist at week24 on MRI using the RAMRIS OMERACT score.

Secondary Objective(s)

To explore the effect on structural damage imaging markers measured aschange from Baseline in dynamic contrast enhanced (DCE)-MRI parametersat Week 24 on MCP joints and wrist. To explore other efficacy outcomesof anti-GM-CSF in RA such as Disease Activity Score 28 based onC-reactive protein (DAS28-CRP) and the American College of Rheumatology(ACR) 20, 50, and 70 criteria. To explore the speed of onset of efficacymeasured as effect on synovitis, bone marrow edema, erosion (RAMRIS) andsynovial perfusion using static and DCE-MRI at Weeks 6 and 12. Toevaluate the safety and tolerability of anti-GM-CSF antibody/MTXcoadministration.

Endpoints

Primary Endpoints

Change from baseline in synovitis, erosion and bone marrow oedema(osteitis), on MRI of the MCP and wrist using the RAMRIS OMERACT at week24.

Secondary Endpoints

To evaluate changes on:

-   -   Vascular perfusion of the synovium measured as a change from        baseline in Dynamic Contrast Enhanced MRI (DCE-MRI) parameters        at week 24. The ability to induce synovial remission (absence of        synovial inflammation) will be assessed at weeks 6 and 12 using        static (RAMRIS OMERACT synovitis score) and DCE-MRI parameters;    -   Proportion of subjects who achieved DAS28-CRP (<2.6) remission        by week 24.    -   Proportion of subjects who achieved DAS28-CRP (<3.2) low disease        activity by week 24.    -   Clinical disease activity measured as decrease in DAS28-CRP from        baseline at all applicable post baseline visits.    -   Proportion of clinical remission defined as SDAI<3.3 at week 24        from baseline.    -   Proportion of low disease activity defined as SDAI<11 at week 24        from baseline.    -   Effect on signs and symptoms measured as proportion of subjects        achieving ACR20, 50 and 70 at all applicable post baseline        visits including visits up to week 40.

Study Subjects

Male and female adults aged 18 years with moderate to severe early RA.

The subjects have

-   -   Swollen joint count (SJC)≥4 and tender joint count (TJC)≥4        (referred to the 28 joint-count system) at Screening and        Baseline Visit; and    -   C-reactive protein (CRP)≥4.3 mg/L at Screening Visit and ESR≥28        mm/hr, and    -   imaging (ultrasound powerdoppler) evidence of moderate to severe        inflammation of at least one MCP joint of the dominant hand or        one joint of the dominant wrist at Screening and Baseline Visit;    -   Received weekly MTX for at least 3 months prior to the Screening        Visit; and    -   Received treatment with MTX≥15-25 mg/week at a stable dose via        the same route of administration and formulation for at least 8        weeks prior to Baseline Visit. or    -   Subject is on a stable dose for at least 8 weeks of MTX of ≥7.5        mg/week is acceptable, if the MTX dose have been reduced for        reasons of documented intolerance to MTX,    -   The subject is willing to continue or initiate treatment with        oral folic acid (at least 5 mg/week) or equivalent and be        treated during the entire trial (mandatory co-medication for MTX        treatment).

Study Medication and Materials

1 ml of anti-GM-CSF-antibody 150 mg/ml solution for subcutaneousinjection was administered to patient participating in the study

Comparator Medication

Adalimumab in an amount of 40 mg administered every other week as asingle dose via subcutaneous injection. Methotrexate was continuedduring treatment with Adalimumab.

Companion Medication

Concomitant treatment with weekly MTX (15-25 mg) at stable doses wascontinued, with appropriate oral folic/(at least 5 mg/week) folinic acidsupplementation or equivalent was continued during the entire study(mandatory co-medication for MTX treatment).

All study medications were administered upon visit of the participatingsubjects in the clinic for dosing of study drug at weeks 0, 2, 6, 10,14, 18 and 22 if assigned to anti-GM-CSF. Subjects assigned to takeadalimumab will visit the clinic for dosing of study drug at weeks 0, 2,4, 6, 8, 10, 12, 14, 16, 18, 20 and 22.

TABLE 1 Doses administered Treatment Group Dose Treatment DescriptionAnti-GM-CSF solution 150 mg/ml 1 ml subcutaneous injection for injectionAdalimumab pre filled  40 mg Subcutaneous injection syringe

Efficacy Measurements

MRI

MRI of the dominate hand and wrist were performed at Baseline and weeks6, 12, and 24. Several MRI images were taken before and after thecontract injection using, Gadolinium.

Ultrasound (US) Powerdoppler

US Powerdoppler was performed on the dominant hand or dominant wrist atscreening and baseline to confirm evidence of moderate to severeinflammation for eligibility.

DAS28-CRP/ESR

The DAS28-CRP score was calculated at screening and baseline and atvisits in weeks 2, 6, 10, 12, 18, 24, 32, and 40.

The Disease Activity Score 28 (DAS28) combines information relating tothe number of swollen and tender joints, in addition to a measure ofgeneral health, and the acute phase response. The DAS28 is amodification of the original DAS and is based on a count of 28 swollenand tender joints and has been used to objectively evaluate a subject'sresponse to treatment. The DAS 28 CRP utilizing joint scores from thefollowing 28 joints: elbows, shoulders, elbow, wrists,metacarpal-phalangeals I-V, proximal interphalangeals I-V and knees. ITis calculated using the following formula:DAS28(CRP)=0.56*√(TJC28)+0.28*√(SJC28)+0.014*GH+0.36*ln(CRP+1)+0.96

Where TJC—Tender joint Count, SJC=Swollen Joint Count, (GH=subjectassessment of disease activity using a 100 mm visual analogue scale(VAS) with 0=best, 100=worst) and CRP=C reactive Protein (in mg/L).

The DAS 28 ESR is very similar to DAS 28 CRP but utilizes ESR(Erythrocyte sedimentation rate) instead of CRP in its below formula.DAS28 (ESR) was measured by the site at randomization to checkeligibility criteria.DAS28(ESR)=0.56*√(TJC28)+0.28*√(SJC28)+0.014*GH+0.70*ln(ESR)+0.70

ESR in mm/hour.

American College of Rheumatology (ACR) Criteria Assessment

ACR Criteria assessment was performed at screening and baseline and atthe visits in weeks 2, 6, 10, 12, 18, 24, 32, and 40.

ACR20/50/70 response rate are included as secondary efficacy endpointsat all applicable post baseline visits including visits up to week 40.Responders will be defined as those subjects whose improvement frombaseline to week 40 fulfils the following criteria:

≥20/50/70% reduction in the TJC (66/68).

≥20/50/70% reduction in the SJC (66/68).

≥20/50/70% reduction in three of the following additional measures:

Patient Global and Physician Global VAS, and HAQ-DI

Patient's/physician's global assessment of disease activity captures thestate of disease over the previous 7 days on the day of the visit.Disease activity will be assessed by both subject and physician using a100 mm VAS (with the endpoints 0=not active at all, and 100=extremelyactive). Subject and physician will mark these points on the scale usingthe electronic site device.

Patient's assessment of pain focused on pain (VAS pain) experienced overthe previous 7 days, as recorded during study site visits. Maximumintensity of pain will be documented, as part of the HAQ-DI, by markingthe respective value on a VAS contained within an electronic site device(100 mm line with the endpoints 0=no pain at all, and 100=very severepain).

The Health Assessment Questionnaire-Disability Index (HAQ-DI)questionnaire will be the basis for the subjects' self-assessment oftheir health status. The HAQ-DI includes eight blocks of questionscovering difficulties encountered in the previous 7 days when performingsimple daily activities, such as personal hygiene (washing, and dressingor undressing), mobility domestic and outdoors (walking, mounting steps,going shopping, carrying things), as well as intake of food or drink andthe handling of tools used in everyday life.

Furthermore, the use of mechanical aids and the need for helpers isqueried. The Investigator will check for plausibility and completenessof entries, without influencing the subjects in their assessments.

Patient Global and Physician Global VAS, and HAQ-DI were performed atscreening and baseline and at the visits in weeks 2, 6, 10, 12, 18, 24,32, and 40.

The EuroQoL Health Questionnaire (EQ-5D) was completed by theparticipants in the study at baseline, and in weeks 6, 12, and 24.

Safety Assessments

Safety assessments will be performed throughout the trial via themonitoring of adverse events (AEs), physical examinations, vital signs,laboratory results (haematology, serum biochemistry, and urinalysis),lung function tests and electrocardiograms (ECGs). In addition, thoroughand extensive monitoring of pulmonary symptoms and signs (includingpulsoximetry and a dyspnea questionnaire, at all visits, and chest x-rayand lung function testing, at selected time points) will be conducted toidentify any signs of potential PAP at an early stage.

What is claimed is:
 1. A method of treating an inflammatory disease in ahuman subject, wherein the inflammatory disease is selected from thegroup consisting of sarcoidosis, systemic lupus erythematosus (SLE),psoriatic arthritis, ankylosing spondylitis, juvenile idiopathicarthritis, and osteoarthritis, comprising administering to the humansubject a neutralizing antibody or a functional fragment thereof thatspecifically binds a primate granulocyte macrophage colony-stimulatingfactor (GM-CSF), wherein the neutralizing antibody or functionalfragment thereof is administered according to the following dosingscheme: i) administering a first initial dose to the human subjectcomprising 300 mg or 150 mg of the neutralizing antibody or a functionalfragment thereof; ii) administering a second dose to the human subjectcomprising 150 mg of the neutralizing antibody or a functional fragmentthereof about 14 days or about 28 days after the first initial dose;iii) administering a third dose to the human subject comprising 150 mgof the neutralizing antibody or a functional fragment thereof about 28days after the second dose; and iv) administering one or more additionaldoses to the human subject comprising 150 mg of the neutralizingantibody or a functional fragment thereof with intervals of about 28days beginning about 28 days after the third dose; wherein theneutralizing antibody or functional fragment thereof comprises a lightchain variable region and a heavy chain variable region, wherein thelight chain variable region comprises a CDR1 comprising the amino acidsequence of SEQ ID NO: 16, a CDR2 comprising the amino acid sequence ofSEQ ID NO: 17, and a CDR3 comprising the amino acid sequence of SEQ IDNO: 18, and wherein the heavy chain variable region comprises a CDR1comprising the amino acid sequence of SEQ ID NO: 14, a CDR2 comprisingthe amino acid sequence of SEQ ID NO: 15, and a CDR3 comprising theamino acid sequence of SEQ ID NO:
 2. 2. The method of claim 1, whereinthe neutralizing antibody or functional fragment thereof is administeredsubcutaneously.
 3. The method of claim 1, wherein the neutralizingantibody or functional fragment thereof is administered subcutaneouslyin at least 5 or at least 7 doses over a period of at least 21 weeks. 4.The method of claim 1, wherein the light chain variable region comprisesthe amino acid sequence of SEQ ID NO: 19, and the heavy chain variableregion comprises the amino acid sequence of SEQ ID NO:
 21. 5. The methodof claim 4, wherein the neutralizing antibody or functional fragmentthereof is formulated for subcutaneous administration.
 6. The method ofclaim 1, wherein the light chain comprises the amino acid sequence ofSEQ ID NO: 34, and the heavy chain comprises the amino acid sequence ofSEQ ID NO:
 35. 7. The method of claim 6, wherein the neutralizingantibody or functional fragment thereof is formulated for subcutaneousadministration.
 8. The method of claim 1, wherein structural jointdamage does not advance for at least 1 year subsequent to the start oftreatment.
 9. The method of claim 1, wherein the human subject receivesat least one additional anti-inflammatory drug selected from the groupconsisting of disease-modifying antirheumatic drugs (DMARDs),corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDS), opioids,and biologic drugs.
 10. The method of claim 9, wherein the at least oneadditional anti-inflammatory drug is an anti-folate compound.
 11. Themethod of claim 10, wherein the anti-folate compound is methotrexate.12. The method of claim 11, wherein the methotrexate is administeredonce weekly.
 13. The method of claim 12, wherein the methotrexate isadministered at a dose of 7.5 to 25 mg per administration.
 14. Themethod of claim 9, wherein the neutralizing antibody or functionalfragment thereof is formulated for subcutaneous administration.